Methods of treating or preventing interstitial cystitis

ABSTRACT

This invention provides methods for the treatment or prevention of interstitial cystitis or urethral syndrome in a mammal which comprise administering to a mammal in need thereof an effective amount of a substituted benzimidazole, or a pharmaceutically acceptable salt or solvate thereof.

This application is a International 371 of PCT/US97/03895 filed Mar. 7,1997. It also claims the benefit of U.S. Provisional Application No.60/013,129 filed Mar. 11, 1996.

BACKGROUND OF THE INVENTION

Tachykinins are a family of peptides which share a common amidatedcarboxy terminal sequence. Substance P was the first peptide of thisfamily to be isolated, although its purification and the determinationof its primary sequence did not occur until the early 1970's.

Between 1983 and 1984 several groups reported the isolation of two novelmammalian tachykinins, now termed neurokinin A (also known as substanceK, neuromedin L, and neurokinin α), and neurokinin B (also known asneuromedin K and neurokinin β). See, J. E. Maggio, Peptides 6(Supplement 3):237-243 (1985) for a review of these discoveries.

Tachykinins are widely distributed in both the central and peripheralnervous systems, are released from nerves, and exert a variety ofbiological actions, which, in most cases, depend upon activation ofspecific receptors expressed on the membrane of target cells.Tachykinins are also produced by a number of non-neural tissues.

The mammalian tachykinins substance P, neurokinin A, and neurokinin Bact through three major receptor subtypes, denoted as NK-1, NK-2, andNK-3, respectively. These receptors are present in a variety of organs.

Substance P is believed inter alia to be involved in theneurotransmission of pain sensations, including the pain associated withmigraine headaches and with arthritis. These peptides have also beenimplicated in gastrointestinal disorders and diseases of thegastrointestinal tract such as inflammatory bowel disease. Tachykininshave also been implicated as playing a role in numerous other maladies,as discussed infra.

Tachykinins play a major role in mediating the sensation andtransmission of pain or nociception, especially migraine headaches. see,e.g., S. L. Shepheard, et al., British Journal of Pharmacology 108:11-20(1993); S. M. Moussaoui, et al., European Journal of Pharmacology,238:421-424 (1993); and W. S. Lee, et al., British Journal ofPharmacology, 112:920-924 (1994).

In view of the wide number of clinical maladies associated with anexcess of tachykinins, the development of tachykinin receptorantagonists will serve to control these clinical conditions. Theearliest tachykinin receptor antagonists were peptide derivatives. Theseantagonists proved to be of limited pharmaceutical utility because oftheir metabolic instability.

Recent publications have described novel classes of non-peptidyltachykinin receptor antagonists which generally have greater oralbioavailability and metabolic stability than the earlier classes oftachykinin receptor antagonists. Examples of such newer non-peptidyltachykinin receptor antagonists are found in U.S. Pat. No. 5,328,927,issued Jul. 12, 1994; U.S. Pat. No. 5,360,820, issued Nov. 1, 1994; U.S.Pat. No. 5,344,830, issued Sep. 6, 1994; U.S. Pat. No. 5,331,089, issuedJul. 19, 1994; European Patent Publication 591,040 A1, published Apr. 6,1994; Patent Cooperation Treaty publication WO 94/01402, published Jan.20, 1994; Patent Cooperation Treaty publication WO 94/04494, publishedMar. 3, 1994; and Patent Cooperation Treaty publication WO 93/011609,published Jan. 21, 1993.

Interstitial cystitis is a chronic debilitating inflammatory disorder ofthe bladder. The disease is most common in women ranging in age fromabout thirty to sixty with onset of the condition typically occurring atabout forty years of age. It is characterized by a number of urinarydifficulties, such as suprapubic pressure and pain, with bladderfilling, urinary frequency, nocturia, dysuria, urgency and irritativevoiding associated with morphological and histological changes in thebladder. The condition is characterized as "interstitial cystitis"because it is believed the condition does not affect the surface of thebladder, but instead involves the spaces between the cells, namely theinterstices, in the lining of the bladder.

Urethral syndrome is a related painful voiding disorder of unknownetiology affecting women exhibiting many of the conditions set forthabove.

As noted in U.S. Pat. No. 5,145,859, issued Sep. 8, 1992, the entirecontents of which are herein incorporated by reference, there are anumber of compounds proposed to treat these conditions, based ondiffering theories as to the etiology of interstitial cystitis andurethral syndrome. None of these treatment regimens has provencompletely successful to date.

Because of the current dissatisfaction of the currently marketedtreatments for interstitial cystitis within the affected population,there exists a need for a more efficacious and safe treatment.

SUMMARY OF THE INVENTION

This invention provides methods for the treatment or prevention ofinterstitial cystitis or urethral syndrome in a mammal which compriseadministering to a mammal in need thereof an effective amount of acompound of Formula I ##STR1## wherein: R¹ is hydrogen, C₁ -C₁₂ alkyl,C₁ -C₆ alkoxy, phenyl, C₃ -C₈ cycloalkyl, naphthyl, heterocyclic,unsaturated heterocyclic, phenyl-(C₁ -C₆ alkylidenyl)-, naphthyl-(C₁ -C₆alkylidenyl)-, heterocyclic-(C₁ -C₆ alkylidenyl)-, unsaturatedheterocyclic-(C₁ -C₆ alkylidenyl)-, phenyl-(C₁ -C₆ alkoxy)-,naphthyl-(C₁ -C₆ alkoxy)-, heterocyclic-(C₁ -C₆ alkoxy)-, or unsaturatedheterocyclic-(C₁ -C₆ alkoxy)-,

any one of which phenyl, naphthyl, heterocyclic, C₃ -C₈ cycloalkyl, orunsaturated heterocyclic groups may be optionally substituted with one,two, or three moieties independently selected from group consisting ofheterocyclic-(C₁ -C₆ alkylidenyl)-, unsaturated heterocyclic-(C₁ -C₆alkylidenyl)-, hydroxy, halo, C₁ -C₆ alkyl, C₁ -C₆ alkoxy,trifluoromethyl, nitro, amino, cyano, C₁ -C₆ alkylamino, and C₁ -C₆alkylthio;

R² is hydrogen, C₁ -C₁₂ alkyl, C₁ -C₆ alkoxy, phenyl, C₃ -C₈ cycloalkyl,naphthyl, heterocyclic, unsaturated heterocyclic, phenyl-(C₁ -C₆alkylidenyl)-, naphthyl-(C₁ -C₆ alkylidenyl)-, heterocyclic-(C₁ -C₆alkylidenyl)-, unsaturated heterocyclic-(C₁ -C₆ alkylidenyl)-,phenyl-(C₁ -C₆ alkoxy)-, naphthyl-(C₁ -C₆ alkoxy)-, heterocyclic-(C₁ -C₆alkoxy)-, or unsaturated heterocyclic-(C₁ -C₆ alkoxy)-,

any one of which phenyl, naphthyl, heterocyclic, C₃ -C₈ cycloalkyl orunsaturated heterocyclic groups may be optionally substituted with one,two, or three moieties independenly selected from group consisting ofphenyl-(C₁ -C₆ alkylidenyl)-, naphthyl-(C₁ -C₆ alkylidenyl)-,heterocyclic-(C₁ -C₆ alkylidenyl)-, unsaturated heterocyclic-(C₁ -C₆alkylidenyl)-, phenyl-(C₁ -C₆ alkoxy)-, naphthyl-(C₁ -C₆ alkoxy)-,heterocyclic-(C₁ -C₆ alkoxy)-, or unsaturated heterocyclic-(C₁ -C₆alkoxy)-, hydroxy, halo, C₁ -C₆ alkyl, C₁ -C₆ alkoxy, trifluoromethyl,nitro, amino, cyano, C₁ -C₆ alkylamino, and C₁ -C₆ alkylthio;

R³ is hydrogen, nitro, C₁ -C₆ alkanoyl, amino, C₁ -C₆ alkyl, C₁ -C₆alkoxy, C₃ -C₈ cycloalkyl, heterocyclic, unsaturated heterocyclic, halo,C₁ -C₆ alkylthio, hydroxy-(C₁ -C₆ alkylidenyl)-, hydroxy-(C₁ -C₆alkylidenyl)amino-, R⁴ R⁵ N-, R⁴ R⁵ N-(C₁ -C₆ alkylidenyl)-, R⁴ R⁵ N-(C₁-C₆ alkoxy)-, hydroxy-(C₁ -C₆ alkyl)-, heterocyclic-(C₁ -C₆ alkoxy)-,amino(C₁ -C₆ alkylidenyl)-, or trifluoromethyl,

where R⁴ and R⁵ are independently selected from the group consisting ofC₁ -C₆ alkyl, C₁ -C₆ alkoxy, C₁ -C₆ alkanoyl, aryl, heterocyclic,unsaturated heterocyclic, aryl(C₁ -C₆ alkylidenyl)-, heterocyclic(C₁ -C₆alkylidenyl)-, unsaturated heterocyclic(C₁ -C₆ alkylidenyl)-, andhydrogen or R⁴ and R⁵ combine to form C₃ -C₈ cycloalkyl,

any one of which alkyl or alkoxy groups may be substituted with one ormore halo, amino, or nitro, and

any one of which aryl, unsaturated heterocyclic, or heterocyclic groupsmay be substituted with one, two, or three moieties independenlyselected from group consisting of hydroxy, halo, C₁ -C₆ alkyl, C₁ -C₆alkoxy, trifluoromethyl, nitro, amino, cyano, C₃ -C₈ cycloalkyl, C₁ -C₆alkylamino, and C₁ -C₆ alkylthio;

with the proviso that not more than one of R¹ and R² may be hydrogen;

or a pharmaceutically acceptable salt or solvate thereof, in combinationwith another analgesic whose primary mechanism of action is not as atachykinin receptor antagonist.

DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS

The terms and abbreviations used in the instant examples have theirnormal meanings unless otherwise designated. For example "°C" refers todegrees Celsius; "N" refers to normal or normality; "mol" refers to moleor moles; "mmol" refers to millimole or millimoles; "g" refers to gramor grams; "kg" refers to kilogram or kilograms; "L" refers to liter orliters; "ml" means milliliter or mililiters; "M" refers to molar ormolarity; "MS" refers to mass spectrometry; and "NMR" refers to nuclearmagnetic resonance spectroscopy.

As used herein, the term "C₁ -C₆ alkyl" refers to straight or branched,monovalent, saturated aliphatic chains of 1 to 6 carbon atoms andincludes, but is not limited to, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, t-butyl, pentyl, isopentyl, and hexyl. The term "C₁ -C₆alkyl" includes within its definition the term "C₁ -C₃ alkyl".

"Halo" represents chloro, fluoro, bromo or iodo.

The term "haloformate" as used herein refers to an ester of a haloformicacid, this compound having the formula ##STR2## wherein X is halo, andR^(d) is C₁ -C₆ alkyl. Preferred haloformates are bromoformates andchloroformates. Especially preferred are chloroformates. Thosehaloformates wherein R^(d) is C₃ -C₆ alkyl are especially preferred.Most preferred is isobutylchloroformate.

The term "unsaturated heterocycle" represents a stable 5- to 7-memberedmonocyclic or 7- to 10-membered bicyclic heterocyclic ring which has oneor more double bonds and which consists of carbon atoms and from one tothree heteroatoms selected from the group consisting of nitrogen, oxygenor sulfur, and wherein the nitrogen and sulfur heteroatoms mayoptionally be oxidized, and the nitrogen heteroatom may optionally bequarternized and including a bicyclic group in which any of theabove-defined heterocyclic rings is fused to a benzene ring. Theunsaturated heterocyclic ring may be attached at any heteroatom orcarbon atom which affords a stable structure.

Examples of such heterocycles and unsaturated heterocycles includepiperidinyl, piperazinyl, azepinyl, pyrrolyl, 4-piperidonyl,pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl,imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl,oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl,thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl,quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazolyl, benzopyranyl,benzothiazolyl, benzoazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl,thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl-sulfoxide,thiamorpholinylsulfone, oxadiazolyl, triazolyl, tetrahydroquinolinyl,and tetrahydroisoquolinyl.

"C₁ -C₆ alkoxy" represents a straight or branched alkyl chain havingfrom one to six carbon atoms attached to an oxygen atom. Typical C₁ -C₆alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy,t-butoxy, pentoxy and the like. The term "C₁ -C₆ alkoxy" includes withinits definition the term "C₁ -C₄ alkoxy".

"C₂ -C₆ alkanoyl" represents a straight or branched alkyl chain havingfrom one to five carbon atoms attached to a carbonyl moiety. Typical C₂-C₆ alkanoyl groups include acetyl, propanoyl, isopropanoyl, butanoyl,t-butanoyl, pentanoyl, hexanoyl, 3-methylpentanoyl and the like.

"C₃ -C₈ cycloalkyl" represents a saturated hydrocarbon ring structurecontaining from three to eight carbon atoms which is unsubstituted.Typical C₃ -C₈ cycloalkyl groups include cyclopropyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl.

The term "hydroxy-protecting groups" as used herein refers tosubstitents of the hydroxy group commonly employed to block or protectthe hydroxy functionality while reacting other functional groups on thecompound. Examples of such hydroxy-protecting groups includemethoxymethyl, benzyloxymethyl, methoxyethoxymethyl,2-(trimethylsilyl)ethoxymethyl, methylthiomethyl,2,2-dichloro-1,1-difluoroethyl, tetrahydropyranyl, phenacyl,cyclopropylmethyl, allyl, C₁ -C₆ alkyl, 2,6-dimethylbenzyl,o-nitrobenzyl, 4-picolyl, dimethylsilyl, t-butyldimethylsilyl,levulinate, pivaloate, benzoate, dimethylsulfonate, dimethylphosphinyl,isobutyrate, adamantoate and tetrahydropyranyl Further examples of thesegroups may be found in T. W. Greene and P. G. M. Wuts, PROTECTIVE GROUPSIN ORGANIC SYNTHESIS, (1991) at Chapter 3.

The compounds prepared in the processes of the present invention have anasymmetric center. As a consequence of this chiral center, the compoundsproduced in the present invention may occur as racemates, mixtures ofenantiomers and as individual enantiomers, as well as diastereomers andmixtures of diastereomers. Processes for preparing such asymmetricforms, individual isomers and combinations thereof, are within the scopeof the present invention.

The terms "R" and "S" are used herein as commonly used in organicchemistry to denote specific configuration of a chiral center. The term"R" (rectus) refers to that configuration of a chiral center with aclockwise relationship of group priorities (highest to second lowest)when viewed along the bond toward the lowest priority group. The term"S" (sinister) refers to that configuration of a chiral center with acounterclockwise relationship of group priorities (highest to secondlowest) when viewed along the bond toward the lowest priority group. Thepriority of groups is based upon their atomic number (in order ofdecreasing atomic number). A partial list of priorities and a discussionof stereochemistry is contained in NOMENCLATURE OF ORGANIC COMPOUNDS:PRINCIPLES AND PRACTICE, (J. H. Fletcher, et al., eds., 1974) at pages103-120.

In addition to the (R)-(S) system, the older D-L system is also used inthis document to denote absolute configuration, especially withreference to amino acids. In this system a Fischer projection formula isoriented so that the number 1 carbon of the main chain is at the top.The prefix "D" is used to represent the absolute configuration of theisomer in which the functional (determining) group is on the right sideof the carbon atom at the chiral center and "L", that of the isomer inwhich it is on the left.

As noted supra, this invention includes methods employing thepharmaceutically acceptable salts of the compounds defined by Formula I.A compound of this invention can possess a sufficiently acidic, asufficiently basic, or both functional groups, and accordingly reactwith any of a number of organic and inorganic bases, and inorganic andorganic acids, to form a pharmaceutically acceptable salt.

The term "pharmaceutically acceptable salt" as used herein, refers tosalts of the compounds of the above formula which are substantiallynon-toxic to living organisms. Typical pharmaceutically acceptable saltsinclude those salts prepared by reaction of the compounds of the presentinvention with a pharmaceutically acceptable mineral or organic acid oran organic or inorganic base. Such salts are known as acid addition andbase addition salts.

Acids commonly employed to form acid addition salts are inorganic acidssuch as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuricacid, phosphoric acid, and the like, and organic acids such asp-toluenesulfonic, methanesulfonic acid, oxalic acid,p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid,benzoic acid, acetic acid, and the like. Examples of suchpharmaceutically acceptable salts are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate,propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate,maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate,methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate,methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,napththalene-2-sulfonate, mandelate and the like. Preferredpharmaceutically acceptable acid addition salts are those formed withmineral acids such as hydrochloric acid and hydrobromic acid, and thoseformed with organic acids such as maleic acid and methanesulfonic acid.

Base addition salts include those derived from inorganic bases, such asammonium or alkali or alkaline earth metal hydroxides, carbonates,bicarbonates, and the like. Such bases useful in preparing the salts ofthis invention thus include sodium hydroxide, potassium hydroxide,ammonium hydroxide, potassium carbonate, sodium carbonate, sodiumbicarbonate, potassium bicarbonate, calcium hydroxide, calciumcarbonate, and the like. The potassium and sodium salt forms areparticularly preferred.

It should be recognized that the particular counterion forming a part ofany salt of this invention is usually not of a critical nature, so longas the salt as a whole is pharmacologically acceptable and as long asthe counterion does not contribute undesired qualities to the salt as awhole.

This invention further encompasses methods employing thepharmaceutically acceptable solvates of the compounds of Formula I. Manyof the compounds of Formula I can combine with solvents such as water,methanol, ethanol and acetonitrile to form pharmaceutically acceptablesolvates such as the corresponding hydrate, methanolate, ethanolate andacetonitrilate.

The term "treating" (or "treat") as used herein includes its generallyaccepted meaning which encompasses prohibiting, preventing, restraining,and slowing, stopping, or reversing progression, severity, or aresultant symptom. As such, the methods of this invention encompass boththerapeutic and prophylactic administration.

The compounds of the present invention are derivatives of benzimidazolewhich are named and numbered according to the Ring Index, The AmericanChemical Society, as follows. ##STR3##

The preferred methods of this invention employ those compounds ofFormula I wherein:

a) R¹ is phenyl, naphthyl, heterocyclic, unsubstituted heterocyclic, orsubstituted derivatives thereof;

b) R² is phenyl, heterocyclic, unsaturated heterocyclic, phenyl(C₁ -C₆alkylidenyl)-, heterocyclic(C₁ -C₆ alkylidenyl)-, unsaturatedheterocyclic(C₁ -C₆ alkylidenyl)-, or substituted derivatives thereof;

c) R³ is R⁴ R⁵ N-(C₁ -C₆ alkylidenyl)-, C₁ -C₆ alkanoyl,, C₁ -C₄ alkoxy,imidazole, amino-(C₁ -C₆ alkylidenyl), hydroxy-(C₁ -C₆alkylidenyl)amino-, heterocyclic-(C₁ -C₆ alkoxy)-, R⁴ R⁵ N-(C₁ -C₆alkoxy)-, or hydroxy;

d) R³ is at the 5 or 6 position of the benzimidazole.

The especially preferred methods of this invention employ thosecompounds of Formula I wherein:

a) R¹ is phenyl or naphthyl substituted with one or more electrondonating, lipophilic substituents;

b) R² is substituted benzyl or substituted phenyl;

c) R³ is R⁴ R⁵ N-(C₁ -C₆ alkylidenyl)-, heterocyclic-(C₁ -C₆ alkoxy)-,R⁴ R⁵ N-(C₁ -C₆ alkoxy)-, or unsaturated heterocyclic(C₁ -C₆alkylidenyl)-; and

d) R³ is at the 6 position of the benzimidazole.

The steps of this synthesis are described in European Patent ApplicationPublication 694,535, to be published Jan. 31, 1996.

The compounds of Formula I can be prepared by processes known in theliterature. See. e.g., G. W. H. Cheeseman and R. F. Cookson, THECHEMISTRY OF THE HETEROCYCLIC COMPOUNDS, (A. Weissberger, et al., eds.1979). The usual process for the preparation of the compounds of FormulaI is by cyclization of an appropriately substituted o-phenylenediaminesuch as the one depicted in Formula III ##STR4## in a solvent or solventmixture. It is generally preferred that the solvent or solvent mixturebe heated, preferably to the boiling point of the solvent. Suitablesolvents include ethanol, isopropanol, glacial acetic acid, benzene,toluene, chlorobenzene, glycol, ethylene glycol, dimethyl ether, diethylether, dimethylformamide, chloroform, ethyl acetate, and the like. It isgenerally preferred to add a condensation agent such as phosphorousoxychloride, thionyl chloride, p-toluenesulfonic acid, hydrochloricacid, sulfuric acid, phosphoric acid, polyphosphoric acid, phosphorouspentoxide, methanesulfonyl hydroxide, methanesulfonyl chloride, and thelike. The cyclization reaction may also optionally be performed in thepresence of a base such as sodium hydroxide, sodium mesylate, orpotassium tert-butylate.

In those compounds in which R² is phenyl a derivative ofN-phenyl-o-phenylenediamine was used as the starting material for thecyclization reaction. The examples if provide sufficient guidance in thepreparation of those compounds of Formula I wherein R³ is hydrogen.

Those compounds of Formula I wherein R³ is not hydrogen, can be preparedby methods taught in the literature. For example, the compounds of thisinvention wherein R³ is C₂ -C₆ alkanoyl can be prepared from theappropriate keto o-phenylenediamine of the formula ##STR5## by methodsknown in the benzimidazole art such as the procedures described in U.S.Pat. No. 4,401,817, issued Aug. 30, 1983, which is herein incorporatedby reference. The method of preparation involves the ammonolysis andreduction of a 4-halo-3-nitrophenyl ketone which is prepared by theFriedel-Crafts reaction of either a 4-halo-3-nitrobenzoyl chloride withan appropriate hydrocarbon or a halobenzene with an appropriate acidchloride followed by aromatic nitration.

Alternatively, the keto benzimidazole reactants can be prepared fromacetanilide by a Friedel-Crafts acylation with the appropriatederivative of C₂ -C₆ alkanoic acid. The resulting 4-keto acetanilide isnitrated to give a 2-nitro-4-ketoacetanilide. The acetanilide ishydrolyzed to give a 2-nitro-4-ketoaniline, which can then becatalytically hydrogenated to yield a 4-keto-o-phenylenediamine whichcan then be ring closed to provide the 5 or 6-substituted benzimidazole.

Those compounds of Formula III wherein R³ is a substituted alkyl oralkylidenyl may be prepared by means of a Friedel-Crafts alkylation withthe appropriate derivative of the R³ moiety using standard procedures,usually employing an alkyl halide or an olefin in the presence of acatalyst such as aluminum chloride, aluminum bromide or another Lewisacid.

An alternative strategy for preparing those compounds of Formula Iwherein R³ is C₁ -C₆ alkoxy, R⁴ R⁵ N-(C₁ -C₆ alkoxy)-, orheterocyclic-(C₁ -C₆ alkoxy)-, or a substituted derivative thereof,involves first reacting a 3-nitro-4-aminophenol with an acyl halide inthe presence of a base ##STR6## to get substitution of the primary amineas well as substitution of the hydroxy group, the ester moiety servingas a hydroxy-protecting group for subsequent reactions. In the next stepof this synthesis the nitro group is then reduced to an amino group,usually by catalytic hydrogenation. ##STR7##

The primary amine of the above compound is then substituted, usuallyusing an aldehyde, such as benzaldehyde or a substituted derivativethereof, followed by hydrogenation, if necessary. In an alternativeembodiment, those compounds of Formula I in which R² is alkyl orsubstituted alkyl may be produced by alkylation of an aromatic aminewith alkyl halide or tosylate, or the like, in the presence of asuitable base, such as trialkylamine, potassium carbonate,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and the like. ##STR8##Cyclization of this substituted phenylenediamine is then performed asdescribed supra, followed by cleavage of the ester group protecting thehydroxy group at the 6-position of the benzimidazole. Suitablecyclization catalysts include phosphorous oxychloride, thionyl chloride,phosphorous pentoxide, phosphorous pentachloride, and other like strongdehydrating agents. ##STR9## A preferred method of cleaving this esteris by incubation of the intermediate in a basic solution, such as 1Nsodium hydroxide, or a weaker base such as potassium carbonate. Thehydroxy group at the 6-position is then substituted using an alkyl oraryl halide, resulting in a compound of Formula I. ##STR10##

The skilled artisan understands that compounds of Formula I substitutedat the 5-position of the benzimidazole can be prepared as describedabove by employing 3-amino-4-nitrophenol as the starting materialinstead of the 3-nitro-4-aminophenol shown supra.

Those compounds of Formula I wherein R² is alkyl or substituted alkylmay alternatively be prepared by the direct alkylation of abenzimidazole wherein the nitrogen at the 1-position is substituted witha hydrogen. This type of alkylation is usually performed by the reactionof the benzimidazole with an alkyl halide in the presence of a strongbase, such as sodium hydride. This reaction is usually performed in apolar aprotic solvent, such as N,N-dimethylformamide, dimethylsulfoxide, dimethylacetamide, hexamethylphosphoric triamide, and thelike.

The following examples further illustrate the preparation of thecompounds of Formula I. The examples are illustrative only and are notintended to limit the scope of the invention in any way. Thedesignations "NMR", "IR", and "MS" in an example indicate that thenuclear magnetic resonance spectrum (NMR), the infrared absorptionspectrum (IR), or the mass as determined by mass spectrometry (MS) wereconsistent with the desired compound.

EXAMPLE 1

Synthesis of 1,2-diphenylbenzimidazole

N-phenyl-o-phenylenediamine (10 mmol, 1.84 grams) was added to diethylether (100 ml) and stirred at room temperature as benzoyl chloride (10mmol, 1.41 g) was added dropwise (a precipitate formed after about onehalf of the benzoyl chloride was added). After addition of the benzoylchloride, the solution was stirred at room temperature for about 15minutes. The reaction mixture was partitioned between aqueous sodiumhydroxide and diethyl ether. The organic layer was removed and theaqueous layer was extracted with ethyl acetate (3×100 ml). The organicfractions were combined and dried over magnesium sulfate. The magnesiumsulfate was filtered out and the solvent removed in vacuo to yield ared/brown solid (2.88 g, 99.8%) which was suitable for use in thecyclization reaction. NMR, mp 136-137° C.

A solution of the intermediate synthesized supra (2.5 g, 8.6 mmol) andphosphorous pentoxide/methanesulfonyl chloride (1:10) (30 ml) was heatedat 100° C. for about one hour. The reaction mixture was then stirredwith ice as 5N sodium hydroxide was added to raise the pH to 14. Thismoisture was then partitioned with ethyl acetate in a separation funnel.The ethyl acetate layer was removed and the aqueous layer was washedwith ethyl acetate (3×100 ml). The organic layers were combined anddried over potassium carbonate overnight. The solution was filtered andthe solvent removed in vacuo to yield 2.2 grams (94.6%) of crudeproduct.

The product was purified by chromatography using a hexanes/ethyl acetate(4:1) solution as the eluent to yield 1.98 grams (85.2%) of the puretitle product. NMR, MS 271(M⁺), mp 108-110° C.

Analysis for C₁₉ H₁₄ N₂ : Theory: C, 84.42; H, 5.22; N, 10.36. Found: C,84.72; H, 5.27; N, 10.35.

EXAMPLE 2

Synthesis of 1-phenyl-2-(4-methoxyphenyl)benzimidazole

A solution of N-phenyl-o-phenylenediamine (10 mmol, 1.84 g) in 100 mldiethyl ether was stirred at room temperature as p-anisoyl chloride (1mmol, 1.71 g) was added dropwise. The resulting mixture was stirred atroom temperature for about 96 hours. A precipitate formed before half ofthe anisoyl chloride/diethyl ether was added.

The resulting reaction mixture was partitioned with 1N sodium hydroxideand the organic layer separated. The aqueous layer was extracted withethyl acetate (3×100 ml). The organic layers were combined and driedover potassium carbonate overnight, filtered, and the solvents wereremoved in vacuo. This yielded 3.57 grams of a dark brown crude product.Further purification could be performed by way of recrystallization frommethylene chloride to yield a homogenous spot as determined bychromatography. mp 147-149° C.

A solution of the intermediate prepared supra (3.19 g, 10 mmol) in 35 mlphosphorous pentoxide/methanesulfonyl chloride (1:10) was stirred at100° C. for about 2.5 hours. The resulting reaction mixture was pouredover ice and stirred as aqueous sodium hydroxide was added. The finalsolution had a pH of 14. This solution was partitioned with ethylacetate. The ethyl acetate layer was removed and the aqueous layer wasextracted with ethyl acetate (3×100 ml). The organic layers werecombined and washed with saturated sodium chloride. This was then driedover potassium carbonate, filtered, concentrated in vacuo to yield abrown/dark red crude product.

This crude product was purified by chromatography using hexanes/ethylacetate (9:1) as eluent to yield 1.38 grams of the title product. NMR,MS 301(M⁺), mp 105-107° C.

Analysis for C₂₀ H₁₆ N₂ O: Theory: C, 79.98; H, 5.37; N, 9.33. Found: C,79.77; H, 5.38; N, 9.11.

EXAMPLE 3

Synthesis of 1-phenyl-2-phenylmethylbenzimidazole

The title intermediate was synthesized in substantial accordance withJournal of Medicinal Chemistry 18:319 (1975). A solution ofN-phenyl-o-phenylenediamine (10 mmol, 1.84 g) and2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (12 mmol, 2.97 g) wasstirred in methylene chloride (60 ml) at room temperature. Phenylaceticacid (10 mmol, 1.36 g) in methylene chloride (30 ml) was added viadropping funnel and stirred at room temperature over a drying tubeovernight. The resulting reaction mixture was partitioned with 6N sodiumhydroxide. The methylene chloride layer was removed and the aqueouslayer was extracted with ethyl acetate (3×100). The organic fractionswere combined, dried over potassium carbonate, filtered and the solventswere removed in vacuo to yield 5.28 grams of a dark red/brown crudeproduct.

The crude product was recrystallized from ethyl acetate and then diethylether to yield a white crystalline product (1.77 g, 58.5%) of the titleproduct. mp 108-110° C.

A portion of the intermediate synthesized supra (1.35 g, 4.5 mmol) and30 ml of phosphorous pentoxide/methane sulfonyl hydroxide (1:10) werestirred at 100° C. for about 6 hours. The resulting reaction mixture waspoured over ice and neutralized with aqueous sodium hydroxide (to pH14). The aqueous layer was partitioned with ethyl acetate and separated.The aqueous layer was extracted with ethyl acetate (4×200 ml). Theorganic layers were combined, dried over potassium carbonate, andfiltered. The solvent was removed in vacuo and the crude dark red/brownproduct was purified by chromatography using hexane/ethyl acetate (9:1)as the eluent. MS 285(M⁺), mp 106-108° C.

Analysis for C₂₀ H₁₆ N₂ O: Theory: C, 84.48; H, 5.67; N, 9.85. Found: C,84.75; H, 5.78; N, 9.93.

EXAMPLE 4

Synthesis of 1-phenyl-2-(3-chlorophenyl)benzimidazole

A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethylether (80 ml) was stirred at room temperature as 3-chlorobenzoylchloride(1.95 g, 11 mmol) in diethyl ether (30 ml) was added dropwise.Precipitate formed almost immediately after total addition of the3-chlorobenzoylchloride. The resulting reaction mixture was stirred atroom temperature for about 3 hours.

The reaction mixture was partitioned with aqueous sodium hydroxide. Theorganic layer was removed and the aqueous layer was extracted with ethylacetate (3×120 ml). The organic layers were combined, dried overpotassium carbonate, and filtered. The solvent was removed in vacuo toyield 3.5 grams of the desired intermediate.

Further purification could be performed using thin layer chromatographywith hexanes/ethyl acetate (9:1) as the eluent. mp 133-134° C., NMR.

A solution of the intermediate prepared supra (2.50 g, 7.7 mmol) and 40ml phosphorous pentoxide/methane sulfonyl hydroxide (1:10) was stirredat 100° C. for about 16 hours. This reaction mixture was then pouredover ice and alkalinized with 5N sodium hydroxide (until pH=14). Thisaqueous solution was then extracted with ethyl acetate (5×150 ml). Theorganic layers were combined and dried over potassium carbonate,filtered, and concentrated in vacuo to yield 2.2 grams of crudered/brown product.

This crude product was further purified by chromatography using ahexanes/ethyl acetate (9:1) solution as the eluent. MS 305, 307, mp107-109° C.

Analysis for C₁₉ H₁₃ ClN₂ : Theory: C, 74.88; H, 4.30; N, 9.19. Found:C, 74.68; H, 4.47; N, 9.25.

EXAMPLE 5

Synthesis of 1-phenyl-2-(4-chlorophenyl)benzimidazole

A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethylether (80 ml) was stirred at room temperature as 4-chlorobenzoylchloride(1.95 g, 11 mmol) in diethyl ether (30 ml) was added dropwise.Precipitate formed almost immediately after total addition of the4-chlorobenzoylchloride. After total addition of the4-chlorobenzoylchloride, the resulting reaction mixture was stirred atroom temperature for about 17 hours.

The reaction mixture was partitioned with 1N sodium hydroxide. Thediethyl ether layer was removed and the aqueous layer extracted withethyl acetate (4×150 ml). The organic layers were combined, dried overpotassium carbonate, filtered, and concentrated in vacuo to yield 3.72grams (>99%) of a dark red/brown solid. The crude product could be usedas is or could be further purified. In the further purification thecrude product was triturated in diethyl ether and filtered to yield anoff-white solid. mp 169-171° C.

A portion of the intermediate synthesized above (crude, 2.84 g) wasstirred in phosphorous pentoxide/methanesulfonyl hydroxide (1:10, 40 ml)at 100° C. for about 16 hours. The reaction mixture was poured over iceand alkalinized with 5N sodium hydroxide (pH=14). The aqueous layer wasextracted with ethyl acetate (5×150 ml). The combined organic fractionswere dried over potassium carbonate, filtered, and concentrated in vacuoto yield 2.52 grams of crude title product. Further purification couldbe accomplished by chromatography to yield a solid yellow crystal.

MS 305, 307, mp 139-141° C.

Analysis for C₁₉ H₁₃ ClN₂ : Theory: C, 74.88; H, 4.30; N, 9.19. Found:C, 74.97; H, 4.33; N, 9.21.

EXAMPLE 6

Synthesis of 1-phenyl-2-(3-methoxyphenyl)benzimidazole

The titled intermediate was prepared essentially as described in Journalof Medicinal Chemistry, 18:319 (1975). A solution ofN-phenyl-o-phenylenediamine (1.84 g, 10 mmol) and m-methoxybenzoic acid(1.52 g, 10 mmol) was stirred at room temperature in methylene chloride(80 ml). N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (2.97 g) wasadded dropwise and the reaction was refluxed for about 16 hours.Additional N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline was added andthe reaction was refluxed for an additional 18 hours.

The reaction mixture was partitioned with 1N sodium hydroxide. Theorganic layer (pH˜14) was extracted with ethyl acetate (3×150 ml). Thecombined organic fractions were dried over potassium carbonate, filteredand concentrated in vacuo. Crude red oil was purified by chromatographyusing hexanes/ethyl acetate (9:1) as the eluent. White solidcrystallized out of several fractions. mp 118-120° C.

A solution of the intermediate prepared above (1.08 g, 3.4 mmol) inchloroform (85 ml) was stirred at room temperature as phosphorousoxychloride (0.52 g, 3.4 mmol) in chloroform (35 ml) was added dropwise.The reaction mixture was then refluxed overnight.

The reaction mixture was partitioned with 1N sodium hydroxide. Theorganic layer was removed and the aqueous layer was extracted withchloroform (3×150 ml). The organic layers were combined, washed with asaturated sodium chloride solution, dried over potassium carbonate,filtered and the solvents were removed in vacuo to yield 1.18 grams(>99%).

The reaction product was further purified by chromatography using ahexanes/ethyl acetate (9:1) solution as eluent. MS 301(M⁺), mp 110-111°C.

Analysis for C₂₀ H₁₆ N₂ O: Theory: C, 79.98; H, 5.37; N, 9.33. Found: C,79.72; H, 5.49; N, 9.39.

EXAMPLE 7

Synthesis of 1-phenyl-2-(4-nitrophenyl)benzimidazole1-phenylamine-2-[(4-nitrophenyl)carbonylamino]benzene

A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethylether (75 ml) was stirred at room temperature as 4-nitrobenzoylchloride(1.86 g, 10 mmol) in diethyl ether (40 ml) was added dropwise. Aprecipitate quickly formed. The reaction was stirred overnight.

The reaction mixture was partitioned with 1N sodium hydroxide and theorganic layer removed. The aqueous layer (pH˜14) was extracted withethyl acetate (3×100 ml). The organic layers were combined, washed withsaturated sodium chloride, dried over potassium carbonate, filtered andconcentrated in vacuo.

The resulting crude product was triturated with diethyl ether andfiltered to yield 2.48 grams of an orange/brown product was homogenousby chromatography. mp 169-171° C.

A solution of the above-prepared intermediate (2.48 g, 7.4 mmol) inchloroform (80 ml) was stirred at room temperature as phosphorousoxychloride (1.13 g, 7.4 mmol) in chloroform (35 ml) was added dropwise.After constant addition the reaction mixture was refluxed overnight.

The reaction mixture was cooled and partitioned with 1 N sodiumhydroxide (pH˜14). The organic layer was separated and the aqueous layerwas extracted with chloroform (3×100 ml). The organic layers werecombined, washed with saturated sodium chloride solution, dried overpotassium carbonate, filtered, and the solvents were removed in vacuo toyield 2.50 grams of a yellow/green solid. The reaction product waspurified by chromatography using a hexanes/ethyl acetate (4:1) solutionas eluent. MS 316(M⁺), mp 175-177° C.

Analysis for C₁₉ H₁₃ N₃ O₂ : Theory: C, 72.37; H, 4.15; N, 13.33. Found:C, 72.67; H, 4.16; N, 13.30.

EXAMPLE 8

Synthesis of 1-(4-chlorophenyl)-2-phenylbenzimidazole

A solution of N-(4-chlorophenyl)-1,2-phenylenediamine (2.19 g, 10 mmol)in diethyl ether (75 ml) was stirred at room temperature as benzoylchloride (1.41 g, 10 mmol) in diethyl ether (30 ml) was added dropwise.A precipitate quickly formed. The reaction mixture was stirred overnightand partitioned with 1N sodium hydroxide.

The organic layer was removed and the aqueous layer (pH˜14) wasextracted with ethyl acetate (3×150 ml). The organic layers werecombined, washed with saturated sodium chloride, dried over potassiumcarbonate, filtered and removed in vacuo. The crude product wastriturated in diethyl ether to yield 1.84 grams (57%) of a white solidwhich was chromatographically homogenous. mp 158-160° C.

A solution of the intermediate prepared supra (0.33 g, 7.2 mmol) inchloroform (80 ml) was stirred at room temperature as phosphorousoxychloride (1.10 g, 7.2 mmol) in chloroform (30 ml) was added dropwise.After the addition was complete the reaction mixture was refluxedovernight. The reaction mixture was alkalinized to pH=14 with 1N sodiumhydroxide and separated.

The aqueous layer was extracted with chloroform (3×10 ml). The organiclayers were combined, washed with a saturated sodium chloride, driedover potassium carbonate, filtered, and the solvents were removed invacuo to yield 2.45 grams of a red/brown oil which solidified uponsetting at room temperature. The product was purified by chromatographyusing a hexanes/ethyl acetate (4:1) as eluent. MS 305, 307, mp 122-123°C.

Analysis for C₁₉ H₁₃ ClN₂ : Theory: C, 74.88; H, 4.30; N, 9.19. Found:C, 75.18; H, 4.30; N, 9.15.

EXAMPLE 9

Synthesis of 1-phenyl-2-(3-trifluoromethylphenyl)-benzimidazole

A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethylether (80 ml) was stirred at room temperature asm-trifluorormethylbenzoyl chloride (2.09 g, 10 mmol) in diethyl ether(30 ml) was added dropwise. The reaction mixture was stirred overnight.

The reaction mixture was partitioned with 1N sodium hydroxide (pH˜14)and the organic layer removed. The aqueous layer was extracted withethyl acetate (3×100 ml). The organic layers were combined, washed witha saturated sodium chloride solution, dried over potassium carbonate,filtered, and the solvents were removed in vacuo to yield a darkred/brown oil which solidified upon standing at room temperature. Thereaction product was purified by chromatography using a hexanes/ethylacetate (4:1) solution as eluent.

A solution of the intermediate prepared above (3.20 g, 9.0 mmol) inchloroform (85 ml) was stirred at room temperature as phosphorousoxychloride (1.78 g, 9 mmol) in chloroform (35 ml) was added dropwise.The reaction mixture was refluxed overnight.

The reaction mixture was partitioned with 1N sodium hydroxide. Theorganic layer was removed and the aqueous layer was extracted withchloroform (3×150 ml). The organic layers were combined, washed with asaturated sodium chloride solution, dried over potassium carbonate,filtered, and the solvents were removed in vacuo to yield 3.00 grams ofa yellow/brown oil which solidified upon standing.

The reaction product was further purified by chromatography using ahexanes/ethyl acetate (9:1 to 4:1) solution as eluent, yielding 1.89grams (62%) of a light yellow solid. MS 339(M⁺), mp 99-101° C.

Analysis for C₂₀ H₁₃ F₃ N₂ : Theory: C, 71.00; H, 3.87; N, 8.28. Found:C, 71.21; H, 4.07; N, 8.42.

EXAMPLE 10

Synthesis of 1-phenyl-2-(3-nitrophenyl)benzimidazole

A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethylether (80 ml) was stirred at room temperature as 3-nitrobenzoyl chloride(1.86 g, 10 mmol) in diethyl ether (30 ml) was added dropwise. Thereaction mixture was stirred overnight at room temperature.

The reaction mixture was partitioned with 1N sodium hydroxide. Theorganic layer was removed and the aqueous layer was extracted with ethylacetate (3×100 ml). The organic layers were combined, washed with asaturated sodium chloride solution, dried over potassium carbonate,filtered, and the solvents were removed in vacuo.

The product was purified by trituration with diethyl ether to yield 2.19g (65.7%) of a yellow solid. mp 127-129° C.

A solution of the intermediate prepared above (2.9 g, 8.7 mmol) inchloroform (85 ml) was stirred at room temperature was phosphorousoxychloride (in 35 ml chloroform) was added dropwise. The reactionmixture was then refluxed overnight.

The reaction mixture was partitioned with 1N sodium hydroxide and theorganic layer was removed. The aqueous layer was extracted withchloroform (3×120 ml). The organic fractions were combined, washed witha saturated sodium chloride solution, dried over potassium carbonate,filtered, and the solvents were removed in vacuo to yield 2.50 grams ofa brown/green solid.

The reaction product was further purified using thin layerchromatography with a hexanes/ethyl acetate (9:1 to 4:1) solution aseluent. MS 316(M⁺), mp 166-168° C.

Analysis for C₁₉ H₁₃ N₃ O₂ : Theory: C, 72.37; H, 4.16; N, 13.33. Found:C, 72.54; H, 4.27; N, 13.55.

EXAMPLE 11

Synthesis of 1-(4-chlorophenyl)-2-(4-chlorophenyl)-benzimidazole

A solution of N-(4chlorophenyl)-1,2-phenylenediamine (2.19 g, 10 mmol)in diethyl ether (85 ml) was stirred at room temperature as4-chlorobenzoyl chloride (1.75 g, 10 mmol) in diethyl ether (35 ml) wasadded dropwise. The reaction mixture was stirred overnight at roomtemperature.

The reaction mixture was partitioned with 1N sodium hydroxide. Theorganic layer was removed and the aqueous layer (pH˜14) was extractedwith ethyl acetate (3×100 ml). The organic fractions were combined,washed with a saturated sodium chloride solution, dried over potassiumcarbonate, filtered, and the solvents were removed in vacuo to yield acrude red/brown solid.

The reaction product was purified by trituration with diethyl ether toyield 2.91 grams (81.5%) of an off-white solid which waschromatographically homogeneous. mp 180-181° C.

A solution of the intermediate prepared above (3.16 g, 8.8 mmol) inchloroform (90 ml) was stirred at room temperature as phosphorousoxychloride (1.36 g, 8.8 mmol) in chloroform (35 ml) was added dropwise.The reaction mixture was then refluxed overnight.

The mixture was partitioned with 1N sodium hydroxide and the organiclayer was removed. The aqueous fraction was extracted with chloroform(3×150 ml). The organic layers were combined, washed with a saturatedsodium chloride solution, dried over potassium carbonate, filtered, andthe solvents were removed in vacuo to yield 2.83 grams of a gray/brownsolid.

The reaction product was further purified by chromatography to yield2.31 grams (77%) of a light pink solid. MS 339, 341, mp 162-164° C.

Analysis for C₁₉ H₁₂ Cl₂ N₂ : Theory: C, 67.27; H, 3.57; N, 8.30. Found:C, 67.45; H, 3.72; N, 8.36.

EXAMPLE 12

Synthesis of 1-phenyl-2-(4-trifluoromethylphenyl)-benzimidazole

A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethylether (85 ml) was stirred at room temperature as4-(trifluoromethyl)benzoyl chloride (2.09 g, 10 mmol) in diethyl ether(30 ml) was added dropwise. The reaction mixture was stirred overnightat room temperature.

The reaction mixture was partitioned with 1N sodium hydroxide. Theorganic layer was removed and the aqueous layer extracted with ethylacetate (3×100 ml). The organic layers were combined, washed with asodium chloride solution, dried over potassium carbonate, filtered, andthe solvents were removed in vacuo to yield a brown/black solid.

The crude product was triturated with diethyl ether and vacuum filteredto yield 2.56 grams (72%) of a yellow solid which was homogeneous onthin layer chromatography. mp 143-145° C.

A solution of the intermediate prepared above (3.25 g, 9.1 mmol) inchloroform (85 ml) was stirred at room temperature as phosphorousoxychloride in chloroform (35 ml) was added dropwise. The reactionmixture was partitioned with 1N sodium hydroxide.

The organic layer was removed and the aqueous layer was extracted withchloroform (3×150 ml). The organic layers were combined, washed with asaturated sodium chloride solution, dried over potassium carbonate,filtered, and the solvents were removed in vacuo to yield a red/brownoil which solidified upon standing.

The reaction product was further purified by chromatography using ahexanes/ethyl acetate (9:1 to 4:1) solution as eluent. Yield: 2.39 grams(77.6%) of a light yellow solid MS 339(M⁺), mp 133-135° C.

Analysis for C₂₀ H₁₃ F₃ N₂ : Theory: C, 71.00; H, 3.87; N, 8.28. Found:C, 71.28; H, 3.99; N, 8.46.

EXAMPLE 13

Synthesis of 1-phenyl-2-(2-naphthyl)benzimidazole

A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) was stirredat room temperature in diethyl ether (85 ml) as naphthoyl chloride (10mmol, 1.91 g) in diethyl ether (35 ml) was added dropwise. The reactionmixture was stirred overnight at room temperature.

The reaction mixture was alkalinized with 1N sodium hydroxide. Theorganic layer was removed. The aqueous layer pH˜14) was extracted withethyl acetate (3×100 ml). The organic fractions were combined, washedwith a saturated sodium chloride solution, dried over potassiumcarbonate, filtered, and the solvents were removed in vacuo to yield ared/brown solid (3.91 g, >99%).

The solid was triturated with diethyl ether and the remaining solid wascollected by vacuum filtration. The reaction product was furtherpurified by chromatography using a hexanes/ethyl acetate (9:1) solutionas eluent. mp 147-149° C.

A solution of the intermediate prepared above (2.4 g, 7.1 mmol) inchloroform (85 ml) was stirred at room temperature as phosphorousoxychloride (1.1 g, 7.1 mmol) in chloroform (35 ml) was added dropwise.After the addition the reaction mixture was refluxed overnight.

The reaction mixture was alkalinized with 1N sodium hydroxide. Theorganic layer was removed and the aqueous layer was extracted withchloroform (3×150 ml). The organic layers were combined, washed with asaturated sodium chloride solution, dried over potassium carbonate,filtered, and the solvents were removed in vacuo to yield 2.38 grams(>99%) of a brown solid.

The reaction product was further purified by chromatography using ahexanes/ethyl acetate solution as the eluent to yield 1.91 grams (84%)of a light yellow solid. MS 321(M⁺), mp 169-170° C.

Analysis for C₂₃ H₁₆ N₂ : Theory: C, 86.22; H, 5.03; N, 8.04. Found: C,86.21; H, 5.24; N, 8.61.

EXAMPLE 14

Synthesis of 1-phenyl-2-(3,5-dimethoxyphenyl)benzimidazole

A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethylether (85 ml) was stirred at room temperature as 3,5-dimethylbenzoylchloride (2.00 g, 1.84 mmol) in diethyl ether (35 ml) was addeddropwise. The reaction mixture was stirred at room temperatureovernight.

The reaction mixture was alkalinized with 1N sodium hydroxide and theorganic layer was removed The aqueous layer was extracted with ethylacetate (3×100 ml). The organic layers were combined, washed with asaturated sodium chloride solution, dried over potassium carbonate,filtered, and the solvents were removed in vacuo to yield 3.46 grams ofa red/brown oil which solidified upon standing.

Further purification of the title intermediate was achieved bychromatography. mp 107-109° C.

A solution of the crude product of the reaction above (2.3 g, 6.6 mmol)in chloroform (85 ml) was stirred at room temperature as phosphorousoxychloride (1.01 g, 6.6 mmol) in chloroform (25 ml) was added dropwise.The reaction mixture was then refluxed overnight.

The reaction mixture was alkalinized with 1N sodium hydroxide. Theorganic layer was removed and the aqueous layer was extracted withmethylene chloride (3×100 ml). The organic layers were combined, washedwith saturated sodium chloride solution, dried over potassium carbonate,filtered, and the solvents were removed in vacuo to yield a red/brownoil which solidified upon standing.

Further purification of the reaction product was accomplished bychromatography, employing a hexanes/ethyl acetate mixture as the eluentto yield 1.91 grams (87.6%) of a light yellow solid.

MS 331(M⁺), mp 98-99° C.

Analysis for C₂₁ H₁₈ N₂ O₂ : Theory: C, 76.34; H, 5.49; N, 8.48. Found:C, 76.17; H, 5.60; N, 8.51.

EXAMPLE 15

Synthesis of 1-phenyl-2-(3,4-dimethoxyphenyl)benzimidazole

A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethylether (85 ml) was stirred at room temperature as 3,4-dimethoxybenzoylchloride (2.01 g, 10 mmol) in 40 ml of diethyl ether was added dropwise.The reaction mixture was then stirred overnight at room temperature.

The reaction mixture was then alkalinized with 1N sodium hydroxide. Theorganic layer was removed and the aqueous layer was extracted withdiethyl ether (3×150 ml). The organic fractions were combined, washedwith a saturated sodium chloride solution, dried over potassiumcarbonate, filtered, and the solvents were removed in vacuo to yield3.11 grams.

This intermediate was further purified by chromatography using ahexanes/ethyl acetate solution as the eluent, followed by triturationwith hexanes to yield a white crystalline solid. mp 159-160° C.

A solution of the intermediate prepared supra (3.11 g, 8.9 mmol) inchloroform (30 ml) was stirred at room temperature as phosphorousoxychloride (1.40 g, 9 mmol) in chloroform (30 ml) was added dropwise.The reaction mixture was then refluxed overnight. The reaction mixturewas partitioned with 1N sodium hydroxide.

The organic fraction was removed and the aqueous phase was extractedwith methylene chloride (3×150 ml). The organic fractions were combined,washed with saturated sodium chloride solution, dried over potassiumcarbonate, filtered, and the solvents were removed in vacuo to yield abrown oil which solidified upon standing.

The crude product was partitioned between 1N hydrochloric acid and ahexanes/ethyl acetate (1:1) solution. The aqueous layer was removed andthe organic layer was extracted with 1N hydrochloric acid (3×100 ml).The aqueous fractions were combined and alkalinized to pH 14 with sodiumhydroxide. This basified solution was extracted with ethyl acetate(5×100 ml). The organic layers were combined, washed with a saturatedsodium chloride solution, dried over potassium carbonate, filtered, andthe solvents were removed in vacuo to yield 1.70 grams (57.8%) of a pinksolid. MS 331(M⁺), mp 114-115° C.

Analysis for C₂₁ H₁₈ N₂ O₂ : Theory: C, 76.34; H, 5.49; N, 8.48. Found:C, 76.31; H, 5.63; N, 8.53.

EXAMPLE 16

Synthesis of 1-phenyl-2-(3,4,5-trimethoxyphenyl)-benzimidazole

A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethylether (90 ml) was stirred at room temperature as 3,4,5-trimethoxybenzoylchloride (2.31 g, 10 mmol) in diethyl ether (40 ml) was added dropwise.The reaction mixture was then stirred overnight at room temperature. Thesolvents were then removed in vacuo leavingN-[(3,4,5-trimethoxyphenyl)carbonyl)-N'-phenyl-phenylenediamine.

The crude intermediate (3.6 g, 9.5 mmol) in chloroform (100 ml) wasstirred at room temperature as phosphorous oxychloride (1.5 g, 9.5 mmol)in chloroform (20 ml) was added dropwise. The reaction mixture was thenstirred at room temperature for about 72 hours.

The reaction mixture was partitioned between 1N hydrochloric acid andethyl acetate. The organic phase was discarded and the aqueous phase wasalkalinized with 1N sodium hydroxide. The aqueous solution was thenextracted with ethyl acetate (3×100 ml). The organic fractions werecombined and dried over potassium carbonate. The solvents were removedin vacuo to yield the title product as a white solid (2.08 g, 61%). MS361(M⁺), mp 139-141° C.

Analysis for C₂₂ H₂₀ N₂ O₃ : Theory: C, 73.32; H, 5.59; N, 7.77. Found:C, 73.17; H, 5.71; N, 7.72.

EXAMPLE 17

Synthesis of 1-(4-chlorophenyl)-2-(4-methoxyphenyl)-benzimidazole

A solution of N-(4-chlorophenyl)-1,2-phenylenediamine (2.13 g, 10 mmol)in diethyl ether (90 ml) was stirred at room temperature as p-anisoylchloride (1.71 g, 10 mmol) in diethyl ether (45 ml) was added dropwise.The mixture was stirred overnight at room temperature.

The reaction mixture was partitioned with 1N sodium hydroxide. Theorganic layer was removed and the aqueous fraction was extracted withethyl acetate (3×150 ml). The organic layers were combined, washed witha saturated sodium chloride solution, dried over potassium carbonate,filtered, and the solvents were removed in vacuo to yield 3.6 grams of abrown/pink solid.

The desired intermediate was further purified by chromatography using ahexanes/ethyl acetate (3:1) solution as the eluent to yield a light pinksolid. mp 162-164° C.

The intermediate prepared above (3.40 grams, 9.6 mmol) was dissolved inchloroform (90 ml). This solution was stirred at room temperature asphosphorous oxychloride in chloroform (40 ml) was added dropwise. Thereaction mixture was refluxed overnight.

The reaction mixture was partitioned with 1N sodium hydroxide and theorganic layer removed. The aqueous fraction was further extracted withmethylene chloride (3×150 ml). The organic layers were combined, washedwith a saturated sodium chloride solution, dried over potassiumcarbonate, filtered, and the solvents were removed in vacuo.

The reaction product was further purified by chromatography to yield2.64 grams (82.1%) of a light pink solid. MS 335, 337, mp 183-185° C.

Analysis for C₂₀ H₁₅ ClN₂ O: Theory: C, 71.75; H, 4.52; N, 8.37. Found:C, 71.67; H, 4.77; N, 8.59.

EXAMPLE 18

Synthesis of 1-phenyl-2-(4-methylphenyl)benzimidazole

A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethylether (85 ml) was stirred at room temperature as p-toluoyl chloride(1.60 g, 10 mmol) in diethyl ether (35 ml) was added dropwise. Thereaction mixture was stirred overnight at room temperature.

The reaction mire was alkalinized with 1N sodium hydroxide. The organiclayer was removed and the aqueous fraction was extracted with ethylacetate (3×150 ml). The organic layers were combined, washed with asaturated sodium chloride solution, dried over potassium carbonate,filtered, and the solvents were removed in vacuo to yield 3.18 grams ofa red/brown solid.

The intermediate was further purified by chromatography using ahexanes/ethyl acetate (9:1) solution as the eluent to yield a yellowsolid. mp 143-145° C.

The intermediate prepared above (2.63 g, 8.6 mmol) was dissolved inchloroform (85 ml). This solution was stirred at room temperature asphosphorous oxychloride (1.35 g, 8.6 mmol) in chloroform (30 ml) wasadded dropwise. The reaction mixture was refluxed overnight.

The reaction mixture was partitioned with 1N sodium hydroxide and theorganic layer removed. The aqueous layer was extracted with methylenechloride (3×150 ml). The organic fractions were combined, washed with asaturated sodium chloride solution, dried over potassium carbonate,filtered and the solvents were removed in vacuo to yield a red/brown oilwhich solidified upon standing.

The reaction product was further purified by chromatography using ahexanes/ethyl acetate (4:1) solution as the eluent. The fractions werecombined, the solvents removed in vacuo and the resulting oil wastriturated with diethyl ether. The title product was recrystallized fromdiethyl ether/hexanes to yield 1.54 grams (63%). MS 285(M⁺)

Analysis for C₂₀ H₁₆ N₂ : Theory: C, 84.48; H, 5.67; N, 9.85. Found: C,85.60; H, 5.94; N, 10.45.

EXAMPLE 19

Synthesis of 1-phenyl-2-(3-methylphenyl)benzimidazole

A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethylether (90 ml) was stirred at room temperature as m-toluoyl chloride(1.55, 10 mmol) in diethyl ether (30 ml) was added dropwise. Thereaction mixture was stirred at room temperature overnight.

The reaction mixture was then alkalinized with 1N sodium hydroxide. Theorganic layer was removed and the aqueous fraction was extracted withethyl acetate (3×150 ml). The organic fractions were combined, washedwith a saturated sodium chloride solution, dried over potassiumcarbonate, filtered, and the solvents were removed in vacuo to yield3.12 grams of a gray/brown solid.

The intermediate was further purified by chromatography. mp 129-130° C.

The intermediate prepared above (2.5 g, 8.3 mmol) in chloroform (95 ml)was stirred at room temperature as phosphorous oxychloride (1.30 g, 8.4mmol) in chloroform (30 ml) was added dropwise. The reaction mixture wasrefluxed overnight.

The reaction mixture was alkalinized with 1N sodium hydroxide and theorganic layer was removed. The aqueous layer was extracted withmethylene chloride (3×150 ml). The organic layers were combined, washedwith a saturated sodium chloride solution, dried over potassiumcarbonate, filtered, and the solvents were removed in vacuo.

The reaction product was further purified by chromatography using ahexanes/ethyl acetate (4:1) solution as eluent. The product wasrecrystallized from hexanes to yield 0.97 grams (41.1%) of a whitesolid.

MS 285(M⁺), mp 69-71° C.

Analysis for C₂₀ H₁₆ N₂ : Theory: C, 84.48; H, 5.67; N, 9.85. Found: C,84.48; H, 5.72; N, 9.80.

EXAMPLE 20

Synthesis of 1-phenyl-2-(4-cyanophenyl)benzimidazole

A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethylether (100 ml) was stirred at room temperature as 4-cyanobenzoylchloride (1.66 g, 10 mmol) in diethyl ether (40 ml) was added dropwise.The reaction mixture was stirred overnight at room temperature.

The reaction mixture was partitioned with 1N sodium hydroxide. Theorganic fraction was removed and the aqueous layer was extracted withethyl acetate (3×150 ml). The combined organic layers were washed with asaturated sodium chloride solution, dried over potassium carbonate,filtered and the solvents were removed in vacuo to yield 3.31 grams of ared/black oily gum.

This oily gum (2.8 g, 8.9 mmol) was dissolved in chloroform (90 ml).This solution was stirred as phosphorous oxychloride (1.40 g, 9.0 mmol)in chloroform (35 ml) was added dropwise. This reaction mixture wasrefluxed overnight.

The reaction mixture was alkalinized with 1N sodium hydroxide. Theorganic layer was removed and the aqueous fraction was extracted withmethylene chloride (3×150 ml). The organic layers were combined, washedwith a saturated sodium chloride solution, dried over potassiumcarbonate, filtered, and the solvents were removed in vacuo to yield ared/brown oil.

The reaction product was further purified by chromatography using ahexanes/ethyl acetate solution as eluent. The title product then wasrecrystallized from ethyl acetate to yield a white solid MS 296(M⁺), mp182-184° C.

Analysis for C₂₀ H₁₃ N₃ : Theory: C, 81.34; H, 4.44; N, 14.23. Found: C,81.55; H, 4.50; N, 14.47.

EXAMPLE 21

Synthesis of 1-phenyl-2-cyclohexylbenzimidazole

A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethylether (85 ml) was stirred at room temperature as cyclohexanecarbonylchloride (1.46 grams, 10 mmol) in diethyl ether (3 ml) was addeddropwise. The reaction mixture was stirred at room temperatureovernight.

The reaction mixture was alkalinized with 1N sodium hydroxide. Theorganic fraction was removed and the aqueous phase was extracted withethyl acetate (3×150 ml). The organic fractions were combined, washedwith saturated sodium chloride solution, dried over potassium carbonate,filtered, and the solvents were removed in vacuo to yield 2.81 grams ofa brown solid. The reaction product was further purified bychromatography to yield N-phenyl-N'-cyclohexylcarbonylphenylenediamineas a yellow solid.

The intermediate prepared above (2.0 g, 7 mmol) was dissolved inchloroform (80 ml). This solution was stirred at room temperature asphosphorous oxychloride (1.05 g, 7 mmol) in chloroform (30 ml) was addeddropwise. The reaction mixture was refluxed overnight.

The reaction mixture was alkalinized with 1N sodium hydroxide. Theorganic layer was removed and the aqueous layer was extracted withmethylene chloride (3×150 ml). The organic fractions were combined,washed with a saturated sodium chloride solution, dried over potassiumcarbonate, filtered, and the solvents were removed in vacuo to yield2.81 grams of a black/red oil which solidified upon standing.

The reaction product was further purified by partitioning between 1Nhydrochloric acid and an ethyl acetate/hexanes (1:1) solution. Theaqueous layer was alkalinized to pH 10 using 1N sodium hydroxide. Theaqueous fraction was then extracted with ethyl acetate (4×250 ml). Theorganic layers were combined, washed with a saturated sodium chloridesolution, dried over potassium carbonate, filtered and the solvents wereremoved in vacuo to yield 1.47 grams (76%) of a light yellow solid MS277(M⁺), mp 99-101° C.

Analysis for C₁₉ H₂₀ N₂ : Theory: C, 82.57; H, 7.29; N, 10.14. Found: C,82.33; H, 7.45; N, 10.21.

EXAMPLE 22

Synthesis of 1-phenyl-2-(2-chlorophenyl)benzimidazole

A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethylether (85 ml) was stirred at room temperature as 2-chlorobenzoylchloride (1.76 g, 10 mmol) in diethyl ether (35 ml) was added dropwise.The reaction mixture was stirred overnight at room temperature.

The reaction mixture was alkalinized with 1N sodium hydroxide and theorganic layer removed. The aqueous phase was extracted with ethylacetate (3×100 ml). The organic fractions were combined, washed with asaturated sodium chloride solution, dried over potassium carbonate,filtered, and the solvents were removed in vacuo to yield 3.2 grams(>99%) of a gray/brown solid.

The crude product prepared supra (2.7 g, 8.4 mmol) was dissolved inchloroform (95 ml). This solution was stirred at room temperature asphosphorous oxychloride (1.3 g, 8.5 mmol) in chloroform (30 ml) wasadded dropwise. The reaction mixture was refluxed overnight and thenpartitioned with 1N sodium hydroxide.

The organic layer was removed and the aqueous phase was extracted withmethylene chloride (3×150 ml). The combined organic layers were washedwith a saturated sodium chloride solution, dried over potassiumcarbonate, filtered, and the solvents were removed in vacuo.

The crude product was further purified by chromatography using ahexanes/ethyl acetate (9:1) solution as the eluent. The recoveredproduct was triturated in hexanes and filtered to yield 1.31 grams(51.2%) of a light yellow solid. MS 305, 307, mp 146-148° C.

Analysis for C₁₉ H₁₃ ClN₂ : Theory: C, 74.88; H, 4.30; N, 9.19. Found:C, 75.16; H, 4.31; N, 9.21.

EXAMPLE 23

Synthesis of 1-phenyl-2-(2-methylphenyl)benzimidazole

A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethylether (90 ml) was stirred at room temperature as o-toluoyl chloride(1.55 g, 10 mmol) in diethyl ether (35 ml) was added dropwise. Thereaction mixture was stirred overnight at room temperature.

The reaction mixture was alkalinized with 1N sodium hydroxide and theorganic layer was removed. The aqueous fraction was extracted with ethylacetate (3×100 ml). The organic fractions were combined, washed with asaturated sodium chloride solution, dried over potassium carbonate,filtered, and the solvents were removed in vacuo.

The reaction product was further purified by chromatography using ahexanes/ethyl acetate (3:1) solution as the eluent. Trituration withhexanes and subsequent filtration yielded a white solid. mp 118-120° C.

The intermediate prepared above (2.52 g, 8.3 mmol) in chloroform (95 ml)was stirred at room temperature as phosphorous oxychloride (1.33 g, 8.4mmol) in chloroform (30 ml) was added dropwise. The reaction mixture wasrefluxed overnight.

The reaction mixture was alkalinized with 1N sodium hydroxide and theorganic layer was removed. The aqueous layer was extracted withmethylene chloride (3×150 ml). The organic layers were combined, washedwith a saturated sodium chloride solution, dried over potassiumcarbonate, filtered, and the solvents were removed in vacuo.

The reaction product was further purified by chromatography using ahexanes/ethyl acetate (9:1 to 4:1) solution as the eluent to yield apale yellow oil. The product was triturated with hexanes to yield alight yellow solid. MS 285(M⁺), mp 99-101° C.

Analysis for C₂₀ H₁₆ N₂ : Theory: C, 84.48; H, 5.67; N, 9.85. Found: C,84.48; H, 5.72; N, 9.80.

EXAMPLE 24

Synthesis of 1-phenyl-2-(2-methoxyphenyl)benzimidazole

A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethylether (90 ml) was stirred at room temperature as 2-methoxybenzoylchloride (1.55 g, 10 mmol) in diethyl ether (35 ml) was added dropwise.The reaction mixture was stirred overnight at room temperature.

The reaction mixture was alkalinized with 1N sodium hydroxide and theorganic layer was removed. The aqueous fraction was extracted with ethylacetate (3×100 ml). The organic fractions were combined, washed with asaturated sodium chloride solution, dried over potassium carbonate,filtered, and the solvents were removed in vacuo.

The reaction product was further purified by chromatography using ahexanes/ethyl acetate (9:1) solution as eluent. The reaction product wasrecrystallized from hexanes. mp 178-180° C.

The intermediate prepared above (2.65 g, 8.3 mmol) in chloroform (95 ml)was stirred at room temperature as phosphorous oxychloride (1.33 g, 8.4mmol) in chloroform (30 ml) was added dropwise. The reaction mixture wasrefluxed overnight.

The reaction mixture was alkalinized with 1N sodium hydroxide and theorganic layer was removed. The aqueous layer was extracted withmethylene chloride (3×150 ml). The organic layers were combined, washedwith a saturated sodium chloride solution, dried over potassiumcarbonate, filtered, and the solvents were removed in vacuo.

The reaction product was further purified by chromatography using ahexanes/ethyl acetate (4:1) solution as eluent to yield 1.64 grams(65.7%) of the title product as a white solid. MS 301(M⁺), mp 159-160°C.

Analysis for C₂₀ H₁₆ N₂ O: Theory: C, 79.98; H, 5.37; N, 9.33. Found: C,80.01; H, 5.36; N, 9.40.

EXAMPLE 25

Synthesis of 1-phenyl-2-(3-cyanophenyl)benzimidazole

A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethylether (90 ml) was stirred at room temperature as 3-cyanobenzoyl chloride(1.66 g, 10 mmol) in diethyl ether (35 ml) was added dropwise. Thereaction mixture was stirred overnight at room temperature.

The reaction mixture was alkalinized with 1N sodium hydroxide and theorganic layer was removed. The aqueous fraction was extracted with ethylacetate (3×100 ml). The organic fractions were combined, washed with asaturated sodium chloride solution, dried over potassium carbonate,filtered, and the solvents were removed in vacuo.

The reaction product was further purified by chromatography using ahexanes/ethyl acetate (4:1) solution as the eluent. The product wasrecrystallized from hexanes to yield a white solid mp 141-143° C.

The intermediate prepared above (2.63 g, 8.3 mmol) in chloroform (95 ml)was stirred at room temperature as phosphorous oxychloride (1.33 g, 8.4mmol) in chloroform (30 ml) was added dropwise. The reaction mixture wasrefluxed overnight.

The reaction mixture was alkalinized with 1N sodium hydroxide and theorganic layer was removed. The aqueous layer was extracted withmethylene chloride (3×150 ml). The organic layers were combined, washedwith a saturated sodium chloride solution, dried over potassiumcarbonate, filtered, and the solvents were removed in vacuo.

The reaction product was further purified by chromatography using ahexanes/ethyl acetate (9:1 to 4:1) solution as eluent. The title productwas recrystallized from hexanes and ethyl acetate. MS 296(M⁺), mp153-154° C.

Analysis for C₂₀ H₁₃ N₃ : Theory: C, 81.34; H, 4.44; N, 14.23. Found. C,81.60; H. 4.45; N, 14.38.

EXAMPLE 26

Synthesis of 1-dimethylaminoethyl-2-phenylbenzimidazole dihydrochloride

A solution of 2-phenylbenzimidazole (0.97 g, 5 mmol) inN,N-dimethylformamide (anhydrous, 20 ml) was stirred at room temperatureunder nitrogen atmosphere. Two equivalents of sodium hydride in 60%dispersion (0.40 g, 10 mmol) was quickly added and the reaction mixturewas allowed to stir under nitrogen. N,N-Dimethylaminoethyl bromidehydrobromide (1.16 g, 5 mmol) in anhydrous N,N-dimethylformamide (12 ml)was added dropwise by syringe to the stirring mixture. The reactionmixture was stirred overnight at room temperature.

The reaction mixture was partitioned between acetic acid and ethylacetate. The organic layer was discarded and the aqueous phase wasextracted with diethyl ether (5×75 ml). All organic fractions werediscarded.

The aqueous phase was alkalinized with 2N sodium hydroxide. Thissolution was then extracted with diethyl ether (4×100 ml). The organicfractions were combined, washed with a saturated sodium chloridesolution, dried over potassium carbonate, filtered, and the solventswere removed in vacuo to yield 1.11 grams of a cloudy oil.

The crude product was stirred with 2N hydrochloric acid in ethanol. Thesolvents were removed in vacuo to yield 1.16 (66.8%) grams of the titleproduct as a white solid. MS 309, mp 228-231° C.

Analysis for C₁₇ H₁₉ N₃ .2 HCl: Theory: C, 60.36; H, 6.26; N, 12.42.Found: C, 60.09; H, 6.22; N, 12.18.

EXAMPLE 27

Synthesis of 1-phenyl-2-(3,4-dichlorophenyl)benzimidazole

A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethylether (90 ml) was stirred at room temperature as 3,4-dichlorobenzoylchloride (2.10 g, 10 mmol) in diethyl ether (35 ml) was added dropwise.The reaction mixture was stirred overnight at room temperature.

The reaction mixture was alkalinized with 1N sodium hydroxide and theorganic layer was removed. The aqueous fraction was extracted with ethylacetate (3×100 ml). The organic fractions were combined, washed with asaturated sodium chloride solution, dried over potassium carbonate,filtered, and the solvents were removed in vacuo.

The reaction product was further purified by chromatography using ahexanes/ethyl acetate (4:1) solution as the eluent. The product wasrecrystallized from hexanes to yield a white solid. mp 146-147° C.

The intermediate prepared above (3.00 g, 8.4 mmol) in chloroform (95 ml)was stirred at room temperature as phosphorous oxychloride (133 g, 8.4mmol) in chloroform (30 ml) was added dropwise. The reaction mixture wasrefluxed overnight.

The reaction mixture was alkalinized with 1N sodium hydroxide and theorganic layer was removed. The aqueous layer was extracted withmethylene chloride (3×150 ml). The organic layers were combined, washedwith a saturated sodium chloride solution, dried over potassiumcarbonate, filtered, and the solvents were removed in vacuo.

The reaction product was further purified by chromatography using ahexanes/ethyl acetate (4:1) solution as eluent. The title product wasrecrystallized from hexanes and ethyl acetate as a white solid. MS 339,341, mp 144-146° C.

Analysis for C₁₉ H₁₂ Cl₂ N₂ : Theory: C, 67.27; H, 3.57; N, 8.26. Found:C, 67.53; H, 3.61; N, 8.13.

EXAMPLE 28

Synthesis of 1-(piperidin-1-ylethyl)-2-phenylbenzimidazoledihydrochloride

A solution of 2-phenylbenzimidazole (0.97 g, 5 mmol) inN,N-dimethylformamide (anhydrous, 20 ml) was stirred at room temperatureunder nitrogen atmosphere. Two equivalents of sodium hydride in 60%dispersion (0.40 g, 10 mmol) was quickly added and the reaction mixturewas allowed to stir under nitrogen. N-(2-chloroethyl)piperidinyl (10mmol) in anhydrous N,N-dimethylformamide (12 ml) was added dropwise bysyringe to the stirring mixture. The reaction mixture was stirredovernight at room temperature.

The reaction mixture was partitioned between acetic acid and ethylacetate. The organic layer was discarded and the aqueous phase wasextracted with diethyl ether (5×75 ml). All organic fractions werediscarded.

The aqueous phase was alkalinized with 2N sodium hydroxide. Thissolution was then extracted with diethyl ether (4×100 ml). The organicfractions were combined, washed with a saturated sodium chloridesolution, dried over potassium carbonate, filtered, and the solventswere removed in vacuo to yield 1.11 grams of a cloudy oil.

This was then stirred in 2N hydrochloric acid in ethanol. The solventswere removed in vacuo, yielding the crude product, which wasrecrystallized twice from an ethyl acetate/ethanol solution. Thesolvents were removed in vacuo to yield 0.95 grams (50.2%) of the titleproduct as a white solid. MS 306

Analysis for C₂₀ H₂₃ N₃.2 HCl: Theory: C, 63.49; H, 6.66; N, 11.11.Found: C, 63.33; H, 6.64; N, 10.92.

EXAMPLE 29

Synthesis of 1-phenyl-2-(4-hydroxyphenyl)benzimidazole

A solution of 1-phenyl-2-(4-methoxyphenyl)benzimidazole(0.60 g, 2.0mmol) in hydrobromic acid (6 ml) and acetic acid (6 ml) was refluxed for40 hours. The reaction mixture was extracted with diethyl ether (5×150ml) at a pH of 3-5. The organic solvents were discarded. The aqueousphase was alkalinized to pH 8-9 and extracted with ethyl acetate (5×150ml). The organic fractions were combined and dried over potassiumcarbonate, then filtered and the solvents were removed in vacuo to yielda white solid. The solid was triturated in diethyl ether and filtered toyield 0.25 grams of the desired product.

Analysis for C₁₉ H₁₄ N₂ O . 0.5 H₂ O: Theory: C, 77.27; H, 5.12; N,9.48. Found: C, 77.56; H, 4.96; N, 9.39.

EXAMPLE 30

Synthesis of 1-phenyl-2-(3-nitro-4-chlorophenyl)-benzimidazole

A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) and4-chloro-3-nitro-benzoic acid (2.07 g, 10 mmol) in anhydroustetrahydrofuran was stirred at room temperature asN-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (3.71 g, 15 mmol) intetrahydrofuran was added dropwise. The reaction was stirred at roomtemperature for about 72 hours.

The reaction mixture was alkalinized with 1N sodium hydroxide. Theaqueous layer was extracted with ethyl acetate (4×100 ml). The organicfractions were combined, dried over potassium carbonate, filtered, andthe solvents removed in vacuo to yield the crude product.

The reaction product was further purified by chromatography using ahexanes/ethyl acetate (4:1) solution as eluent.

The intermediate prepared above (3.00 g, 8.4 mmol) in chloroform (95 ml)was stirred at room temperature as phosphorous oxychloride (1.33 g, 8.4mmol) in chloroform (30 ml) was added dropwise. The reaction mixture wasrefluxed overnight.

The reaction mixture was alkalinized with 1N sodium hydroxide and theorganic layer was removed. The aqueous layer was extracted withmethylene chloride (3×150 ml). The organic layers were combined, washedwith a saturated sodium chloride solution, dried over potassiumcarbonate, filtered, and the solvents were removed in vacuo.

The reaction product was further purified by chromatography using ahexanes/ethyl acetate (9:1) solution as eluent. The title product wasrecrystallized from fractions with ethyl acetate as a white solid. MS349, 351, mp 179-182° C.

Analysis for C₁₉ H₁₂ ClN₃ O₂ : Theory: C, 65.24; H, 3.46; N, 12.01.Found: C, 65.50; H, 3.51; N, 12.06.

EXAMPLE 31

Synthesis of 1-[2-(morpholin-4-yl)ethyl]-2-phenylbenzimidazoledihydrochloride

A solution of 2-phenylbenzimidazole (0.97 g, 5 mmol) inN,N-dimethylformamide (anhydrous, 20 ml) was stirred at 60° C. undernitrogen atmosphere. Two equivalents of sodium hydride in 60% dispersion(0.40 g, 10 mmol) was quickly added and the reaction mixture was allowedto stir under nitrogen. N-(2-chloroethyl)morpholine (0.93 g, 5 mmol) inanhydrous N,N-dimethylformamide (12 ml) was added dropwise by syringe tothe stirring mixture. The reaction mixture was stirred overnight at 60°C.

The reaction mixture was partitioned between acetic acid and ethylacetate. The organic layer was discarded and the aqueous phase wasextracted with diethyl ether (5×75 ml). All organic fractions werediscarded.

The aqueous phase was alkalinized with 2N sodium hydroxide. Thissolution was then extracted with diethyl ether (4×100 ml). The organicfractions were combined, washed with a saturated sodium chloridesolution, dried over potassium carbonate, filtered, and the solventswere removed in vacuo to yield a cloudy oil.

The crude product was mixed with a 2N hydrochloric acid/ethanol (1:1)solution. The solvents were removed in vacuo to yield 1.52 grams (40%)of a white solid. MS 308.

Analysis for C₁₉ H₂₁ N₃ O . 2 HCl . EtOH: Theory: C, 59.16; H, 6.86; N,9.85. Found: C, 59.20; H, 6.85; N, 9.89.

EXAMPLE 32

Synthesis of 1-phenyl-2-propylbenzimidazole

A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) intetrahydrofuran (90 ml) was stirred at room temperature under a nitrogenatmosphere as butanoyl chloride (1.28 g, 12 mmol) in tetrahydrofuran (35ml) was added dropwise. The reaction mixture was stirred overnight atroom temperature.

The reaction mixture was alkalinized with 1N sodium hydroxide and theorganic layer was removed. The aqueous fraction was extracted with ethylacetate (3×100 ml). The organic fractions were combined, washed with asaturated sodium chloride solution, dried over potassium carbonate,filtered, and the solvents were removed in vacuo.

The reaction product was further purified by chromatography using ahexanes/ethyl acetate (3:1) solution as the eluent. The product wasrecrystallized from hexanes to yield a white solid.

The intermediate prepared above in chloroform was stirred at roomtemperature as an equimolar amount of phosphorous oxychloride inchloroform was added dropwise. The reaction mixture was refluxedovernight.

The reaction mixture was alkalinized with 1N sodium hydroxide and theorganic layer was removed. The aqueous layer was extracted withmethylene chloride (3×150 ml). The organic layers were combined, washedwith a saturated sodium chloride solution, dried over potassiumcarbonate, filtered, and the solvents were removed in vacuo.

The reaction product was further purified by chromatography using ahexanes/ethyl acetate (3:1) solution as eluent. The title product wasrecrystallized from hexanes and ethyl acetate as a white solid, yielding1.55 grams (66%). MS 237, mp 53-55° C.

Analysis for C₁₆ H₁₆ N₂ : Theory: C, 81.32; H, 6.82; N, 11.85. Found: C,81.06; H, 6.69; N, 12.02.

EXAMPLE 33

Synthesis of 1-phenyl-2-(thien-2-yl)benzimidazole

A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethylether (90 ml) was stirred at room temperature under a nitrogenatmosphere as an equimolar amount of 2-chlorocarbonylthiophene indiethyl ether (35 ml) was added dropwise. The reaction mixture wasstirred overnight at room temperature.

The reaction mixture was alkalinized with 1N sodium hydroxide and theorganic layer was removed. The aqueous fraction was extracted with ethylacetate (3×100 ml). The organic fractions were combined, washed with asaturated sodium chloride solution, dried over potassium carbonate,filtered, and the solvents were removed in vacuo to yield a red/brownoil.

The reaction product was further purified by trituration in diethylether. Recrystallization from ethyl acetate yielded a white solid whichwas homogeneous on thin layer chromatography. mp 150-152° C.

The intermediate prepared above in chloroform was stirred at roomtemperature as an equimolar amount of phosphorous oxychloride inchloroform was added dropwise. The reaction mixture was refluxedovernight.

The reaction mixture was alkalinized with 1N sodium hydroxide and theorganic layer was removed. The aqueous layer was extracted withmethylene chloride (3×150 ml). The organic layers were combined, washedwith a saturated sodium chloride solution, dried over potassiumcarbonate, filtered, and the solvents were removed in vacuo.

The reaction product was further purified by chromatography using ahexanes/ethyl acetate (3:1) solution as eluent. The title product wasrecrystallized from hexanes and ethyl acetate as clear crystals. Thesolvent was removed in vacuo, yielding 1.70 grams (64%). MS 277, mp118-120° C.

Analysis for C₁₇ H₁₂ N₂ S: Theory: C, 73.62; H, 4.72; N, 10.10. Found:C, 73.84; H, 4.48; N, 10.30.

EXAMPLE 34

Synthesis of 1-phenyl-2-(3-hydroxyphenyl)benzimidazole

A solution of 1-phenyl-2-(3-methoxyphenyl)benzimidazole (0.20 g, 0.67mmol) and hydrobromic acid (4 ml) and acetic acid (4 ml) was refluxedfor 48 hours. The reaction mixture was cooled and extracted with diethylether (5×150 ml) at pH 3-5. The organic fractions were discarded. Theaqueous phase was alkalinized to pH 8-9 and extracted with ethyl acetate(5×150 ml). The organic layers were combined, washed with a saturatedsodium chloride solution, dried over magnesium sulfate, filtered, andthe solvents were removed in vacuo to yield a white solid. The solid wastriturated with an ethyl acetate/diethyl ether mixture.

The reaction product was further purified by chromatography to yield0.17 grams (88.6%) of a white solid. MS 287(M⁺), mp 245-247°C.

Analysis for C₁₉ H₁₄ N₂ O . 2 H₂ O: Theory: C, 78.71; H, 5.01; N, 9.66.Found: C, 78.79; H, 5.16; N, 9.70.

EXAMPLE 35

Synthesis of 1-phenyl-2-pentylbenzimidazole hydrochloride

A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethylether (90 ml) was stirred at room temperature as an equimolar amount ofhexanoyl chloride in diethyl ether (35 ml) was added dropwise. Thereaction mixture was stirred overnight at room temperature.

The reaction mixture was alkalinized with 1N sodium hydroxide and theorganic layer was removed. The aqueous fraction was extracted with ethylacetate (3×100 ml). The organic fractions were combined, washed with asaturated sodium chloride solution, dried over potassium carbonate,filtered, and the solvents were removed in vacuo to yield a red/brownoil.

The reaction product was further purified by trituration in diethylether. Recrystallization from ethyl acetate yielded a white solid whichwas homogeneous on thin layer chromatography.

The intermediate prepared above in chloroform was stirred at roomtemperature as an equimolar amount of phosphorous oxychloride inchloroform was added dropwise. The reaction mixture was refluxedovernight.

The reaction mixture was alkalinized with 1N sodium hydroxide and theorganic layer was removed. The aqueous layer was extracted withmethylene chloride (3×150 ml). The organic layers were combined, washedwith a saturated sodium chloride solution, dried over potassiumcarbonate, filtered, and the solvents were removed in vacuo to yield ared/brown oil.

The reaction product was further purified by chromatography using ahexanes/ethyl acetate (3:1) solution as eluent to yield 1.82 grams(69.2%) as a red oil. The red oil was stirred in a 2N hydrochloricacid/ethanol (1:1) solution for ten minutes. The ethanol was removed invacuo to yield 2.1 grams of a brown/green solid. The title product wasrecrystallized from an ethyl acetate/ethanol (1:1) solution. The solventwas removed in vacuo, yielding 1.56 grams (51.9%) of the title productas a white solid. MS 265(M⁺), mp 202-205° C.

Analysis for C₁₈ H₂₀ N₂.HCl: Theory: C, 71.87; H, 7.04; N, 9.31. Found:C, 72.02; H, 7.23; N, 9.05.

EXAMPLE 36

Synthesis of 1-phenyl-2-(2-trifluoromethylphenyl)-benzimidazole

A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethylether (90 ml) was stirred at room temperature as an equimolar amount of2-trifluoromethylbenzoyl chloride in diethyl ether (35 ml) was addeddropwise. The reaction mixture was stirred overnight at roomtemperature.

The reaction mixture was alkalinized with 1N sodium hydroxide and theorganic layer was removed. The aqueous fraction was extracted with ethylacetate (3×100 ml). The organic fractions were combined, washed with asaturated sodium chloride solution, dried over potassium carbonate,filtered, and the solvents were removed in vacuo to yield a red/brownoil.

The reaction product was further purified by trituration in diethylether to yield a white solid which was homogeneous on thin layerchromatography. mp 161-162° C.

The intermediate prepared above in chloroform was stirred at roomtemperature as an equimolar amount of phosphorous oxychloride inchloroform was added dropwise. The reaction mixture was refluxedovernight.

The reaction mixture was alkalinized with 1N sodium hydroxide and theorganic layer was removed. The aqueous layer was extracted withmethylene chloride (3×150 ml). The organic layers were combined, washedwith a saturated sodium chloride solution, dried over potassiumcarbonate, filtered, and the solvents were removed in vacuo to yield ared/brown mixture of oil and solid.

The reaction product was further purified by chromatography using ahexanes/ethyl acetate (3:1) solution as eluent followed by triturationin diethyl ether to yield 1.07 grams (37.2%). Recrystallization fromhexanes yielded white crystals, homogeneous on thin layerchromatography. MS 338, mp 142-144° C.

Analysis for C₂₀ H₁₃ F₃ N₂ : Theory: C, 71.00; H, 3.87; N, 8.28. Found:C, 70.70; H, 3.97; N, 8.12.

EXAMPLE 37

Synthesis of 1-benzyl-2-(3,4,5-trimethoxyphenyl)-benzimidazole

A solution of o-phenylenediamine dihydrochloride (3.62 g, 20 mmol),3,4,5-trimethoxybenzaldehyde (3.92 g, 20 mmol) and triethylamine (2.02g, 20 moles) in nitrobenzene (100 mls) was heated at 150° C. for 32hours. The majority of the nitrobenzene was distilled off by vacuumdistillation (60° C. pot temperature, 0.1 mm Hg). The crude product waspartitioned between 1N sodium hydroxide and ethyl acetate. The ethylacetate fraction was removed and the aqueous phase was extracted withethyl acetate (3×100 ml).

The organic fractions were combined, washed with brine, dried oversodium sulfate, filtered, and the solvents were removed in vacuo toyield a red brown oil which was purified by column chromatography usinga hexanes/ethyl acetate (1:1) solution as the eluting solvent to yieldthe intermediate 2-(3,4,5-trimethoxyphenyl)benzimidazole. NMR

The intermediate prepared above (0.91 g, 3.2 mmol) and sodium hydride(0.26 g, 6.4 mmol) in N,N-dimethylformamide (25 ml) were stirred at roomtemperature as benzyl bromide (0.60 g, 6.4 mmol) was added dropwise. Theresulting mixture was stirred at room temperature for 30 minutes andthen heated to 120° C. where it was maintained for seven days.Additional sodium hydride and benzymbromide were added as needed forcethe reaction forward.

The crude product was partitioned between water and ethyl acetate,followed by an acid/base workup in a separatory funnel. The organiclayers were washed with brine, dried over potassium carbonate, filtered,and the solvents were removed in vacuo. MS 375(M⁺)

Analysis for C₂₃ H₂₂ N₂ O₃ : Theory: C, 73.78; H, 5.92; N, 7.48. Found:C, 73.99; H, 5.95; N, 7.19.

EXAMPLES 38 AND 39

Synthesis of1-phenylmethyl-2-(3,4,5-trimethoxyphenyl)-5-methoxybenzimidazole(Example 38) and1-phenylmethyl-2-(3,4,5-trimethoxyphenyl)-6-methoxybenzimidazole(Example 39)

This synthesis was performed essentially as described in Example 37except for the substitution of 4-methoxy-o-phenylenediamine in place ofthe o-phenylenediamine employed there. This resulted in a mixture of theregioisomers of the title products which could be separated using commontechniques.

EXAMPLE 38: MS 404, Analysis for C₂₄ H₂₄ N₂ O₄ : Theory: C, 71.27; H,5.98; N, 6.92. Found: C, 71.07; H, 6.16; N, 6.89.

EXAMPLE 39: MS 404, Analysis for C₂₄ H₂₄ N₂ O₄ : Theory: C, 71.27; H,5.98; N, 6.93. Found: C, 71.24; H, 6.11; N, 6.97.

EXAMPLE 40

Synthesis of 1-(3-chlorobenzyl)-2-(3,4,5-trimethoxyphenyl)-benzimidazole

An amount of 2-(3,4,5-trimethoxyphenyl)-benzimidazole (1.05 g, 3.69mmol), prepared as described in Example 37, supra, was added to athree-neck flask with a stir bar. The contents of the flask were placedunder nitrogen atmosphere and 50 ml of N,N-dimethylformamide was addedby syringe. This mixture was then allowed to stir. Sodium hydride (60%,0.41 g, 4.10 mmol) was then added to the reaction mixture and theresulting mixture was stirred for about 30 minutes.

The resulting grayish mixture was then placed into an oil bath and3-chlorobenzyl bromide (0.60 ml, 4.10 mmol) was added. The temperatureof the solution was then raised to 60° C. and the solution was allowedto stir overnight.

The solution was then removed from the oil bath and allowed to cool toroom temperature. Ethyl acetate (150 ml) was then added to the reactionmixture. This organic solution was extracted with water (3×150 ml),followed by 25 ml of diethyl ether. The organic phase was then washedwith a saturated sodium chloride solution.

The organic solution was reduced in vacuo to yield a yellow oil. To thisoil ethanol (50 ml) and hexanes (20 ml) were added. The yellow solutionwas cooled and allowed to crystallize. The crystals were recovered byfiltration and then washed with 20 ml of hexanes. The liquors werereduced in vacuo and allowed to crystallize to yield a total of 1.05grams of the title product. MS 409, 411, mp 83° C.

Analysis for C₂₃ H₂₁ ClN₂ O₃ : Theory: C, 67.56; H, 5.18; N, 6.85.Found: C, 67.82; H, 5.21; N, 6.64.

EXAMPLE 41

Synthesis of 1-(2-chlorobenzyl)-2-(3,4,5-trimethoxyphenyl)-benzimidazole

The title product was prepared essentially as described in Example 40,supra, except that 2-chlorobenzyl bromide (0.50 ml, 4.19 mmol) wasemployed instead of the 3-chlorobenzyl bromide, to yield 1.13 g (80%).MS 409, 411, mp 173.5° C.

Analysis for C₂₃ H₂₁ ClN₂ O₃ : Theory: C, 67.56; H, 5.18; N, 6.85.Found: C, 67.33; H, 5.21; N, 6.60.

EXAMPLE 42

Synthesis of 1-(4-chlorobenzyl)-2-(3,4,5-trimethoxyphenyl)-benzimidazole

The title compound was prepared essentially as described in Example 40,supra, except that 4-chlorobenzyl bromide (0.75 g, 4.03 mmol) wasemployed instead of the 3-chlorobenzyl bromide. MS 409, 411, mp 169° C.

Analysis for C₂₃ H₂₁ ClN₂ O₃ : Theory: C, 67.56; H, 5.18; N, 6.85.Found: C, 68.07; H, 5.34; N, 6.46.

EXAMPLE 43

Synthesis of 1-(2-methylbenzyl)-2-(3,4,5-trimethoxyphenyl)-benzimidazole

The title compound was prepared essentially as described in Example 40,supra, except that α-bromo-o-xylene (0.55 g, 4.10 mmol) was employedinstead of the 3-chlorobenzyl bromide. MS 389, mp 140.5° C.

Analysis for C₂₄ H₂₄ N₂ O₃ : Theory: C, 74.21; H, 6.23; N, 7.21. Found:C, 73.92; H, 6.25; N, 7.05.

EXAMPLE 44

Synthesis of 1-(3-methylbenzyl)-2-(3,4,5-trimethoxyphenyl)-benzimidazole

The title compound was prepared essentially as described in Example 40,supra, except that α-bromo-m-xylene (0.55 g, 4.10 mmol) was employedinstead of the 3-chlorobenzyl bromide. MS 389, mp 78° C.

Analysis for C₂₄ H₂₄ N₂ O₃ : Theory: C, 74.21; H, 6.23; N, 7.21. Found:C, 73.96; H, 6.34; N, 7.01.

EXAMPLE 45 Synthesis of1-(3-methoxybenzyl)-2-(3,4,5-trimethoxyphenyl)-benzimidazole

The title compound was prepared essentially as described in Example 40,supra, except that 3-methoxybenzyl chloride (0.60 ml, 4.13 mmol) wasemployed instead of the 3-chlorobenzyl bromide. MS 405, mp 127° C.

Analysis for C₂₄ H₂₄ N₂ O₄ : Theory: C, 71.27; H, 5.98; N, 6.93. Found:C, 71.21; H, 6.04; N, 6.98.

EXAMPLE 46

Synthesis of 1-(4methoxybenzyl)-2-(3,4,5-trimethoxyphenyl)-benzimidazole

The title compound was prepared essentially as described in Example 40,supra, except that 4-methoxybenzyl chloride (0.60 ml, 4.13 mmol) wasemployed instead of the 3-chlorobenzyl bromide. MS 405, mp 110.5° C.

Analysis for C₂₄ H₂₄ N₂ O₄ : Theory: C, 71.27; H, 5.98; N, 6.93. Found:C, 71.01; H, 6.01; N, 7.08.

EXAMPLE 47

Synthesis of1-(2-methoxybenzyl)-2-(3,4,5-trimethoxyphenyl)-benzimidazole

The title compound was prepared essentially as described in Example 40,supra, except that 2-methoxybenzyl chloride (50% 1.26 ml, 4.13 mmol) wasemployed instead of the 3-chlorobenzyl bromide. This reaction wasperformed at room temperature and allowed to stir for about six hours.MS 405, mp 136° C.

Analysis for C₂₄ H₂₄ N₂ O₄ : Theory: C, 71.27; H, 5.98; N, 6.93. Found:C, 71.47; H, 6.13; N, 6.92.

EXAMPLE 48

Synthesis of 1-(2-fluorobenzyl)-2-(3,4,5-trimethoxyphenyl)-benzimidazole

The title compound was prepared essentially as described in Example 40,supra, except that 2-fluorobenzyl bromide (0.48 ml, 4.33 mmol) wasemployed instead of the 3-chlorobenzyl bromide. MS 392, mp 153.5° C.

Analysis for C₂₃ H₂₁ FN₂ O₃ : Theory: C, 70.40; H, 5.39; N, 7.14. Found:C, 70.15; H, 5.37; N, 7.14.

EXAMPLE 49

Synthesis of1-(2-trifluoromethylbenzyl)-2-(3,4,5-trimethoxyphenyl)-benzimidazole

The title compound was prepared essentially as described in Example 40,supra, except that 2-trifluoromethylbenzyl bromide (0.48 ml, 4.33 mmol)was employed instead of the 3-chlorobenzyl bromide. MS 442, mp 144° C.

Analysis for C₂₄ H₂₁ F₃ N₂ O₃ : Theory: C, 65.15; H, 4.78; N, 6.33.Found: C, 65.18; H, 4.75; N, 6.28.

EXAMPLE 50

Synthesis of 1-(2-iodobenzyl)-2-(3,4,5-trimethoxyphenyl)-benzimidazole

The title compound was prepared essentially as described in Example 40,supra, except that 2-iodobenzyl bromide (1.0 ml, 4.33 mmol) was employedinstead of the 3-chlorobenzyl bromide. MS 500, mp 179° C.

Analysis for C₂₃ H₂₁ IN₂ O₃ : Theory: C, 55.21; H, 4.23; N, 5.60. Found:C, 55.26; H, 4.27; N, 5.71.

EXAMPLE 51

Synthesis of 1-(2-bromobenzyl)-2-(3,4,5-trimethoxyphenyl)-benzimidazole

The title compound was prepared essentially as described in Example 40,supra, except that 2-bromobenzyl bromide (1.0 ml, 4.33 mmol) wasemployed instead of the 3-chlorobenzyl bromide. MS 452, 454, mp 152° C.

Analysis for C₂₃ H₂₁ BrN₂ O₃ : Theory: C, 60.94; H, 4.67; N, 6.18.Found: C, 61.18; H, 4.62; N, 6.09.

EXAMPLE 52

Synthesis of1-(2,6-dichlorobenzyl)-2-(3,4,5-trimethoxyphenyl)-benzimidazole

The title compound was prepared essentially as described in Example 40,supra, except that 2,6-dichlorobenzyl bromide (0.81 g, 4.10 mmol) wasemployed instead of the 3-chlorobenzyl bromide. mp 157° C. MS 443, 445,NMR, IR.

Analysis for C₂₃ H₂₀ Cl₂ N₂ O₃ : Theory: C, 62.31; H, 4.55; N, 6.32.Found: C, 62.84; H, 4.57; N, 6.31.

EXAMPLE 53

Synthesis of1-(3,4-dichlorobenzyl)-2-(3,4,5-trimethoxyphenyl)-benzimidazole

The title compound was prepared essentially as described in Example 40,supra, except that 3,4-dichlorobenzyl bromide (0.90 g, 4.45 mmol) wasemployed instead of the 3-chlorobenzyl bromide. mp 145° C., MS 443, 445,NMR, IR.

Analysis for C₂₃ H₂₀ Cl₂ N₂ O₃ : Theory: C, 62.31; H, 4.55; N, 6.32.Found: C, 62.35; H, 4.65; N, 6.17.

EXAMPLE 54

Synthesis of1-(2,4-dichlorobenzyl)-2-(3,4,5-trimethoxyphenyl)-benzimidazole

The title compound was prepared essentially as described in Example 40,supra, except that 2,4-dichlorobenzyl bromide (0.45 g, 2.23 mmol) wasemployed instead of the 3-chlorobenzyl bromide. mp 186° C. MS 443, 445,NMR, IR.

Analysis for C₂₃ H₂₀ Cl₂ N₂ O₃ : Theory: C, 62.31; H, 4.55; N, 6.32.Found: C, 62.22; H, 4.65; N, 6.34.

EXAMPLE 55

Synthesis of 1-(4-methylbenzyl)-2-(3,4,5-trimethoxyphenyl)-benzimidazole

The title compound was prepared essentially as described in Example 40,supra, except that 4-methylbenzyl bromide (0.45 g, 2.23 mmol) wasemployed instead of the 3-chlorobenzyl bromide. MS 389, mp 84.5° C.

Analysis for C₂₄ H₂₄ N₂ O₃ : Theory: C, 74.21; H, 6.23; N, 7.21. Found:C, 73.91; H, 6.23; N, 6.98.

EXAMPLE 56

Synthesis of 1-(2-chlorobenzyl)-2-(3-methylphenyl)-benzimidazole

The intermediate 2-(3-methylphenyl)-benzimidazole was prepared by firstmixing reacting 1-amino-2-nitrobenzene (8.50 g, 61.54 mmol) with toluene(180 ml) and heating to 100° C. To this mixture was then added 20 ml ofN,N-diethylaniline and the reaction vessel was placed under a nitrogenatmosphere. To this solution was then added 3-methylbenzoyl chloride (24ml, 132 mmol) and this mixture was then stirred overnight.

After stirring, the reaction mixture was neutralized by the addition of300 ml of 1N hydrochloric acid and 300 ml of ethyl acetate. This wasthen stirred for about 30 minutes. The organic phase was then removedand washed with water, followed by drying over magnesium sulfate andreduction in vacuo, yielding yellow crystals of the intermediate1-[(3-methylphenyl)carbonylamino]-2-nitrobenzene. The nitro group of theabove intermediate was then reduced by catalytic hydrogenation employinga palladium on activated carbon catalyst resulting in the substituted1,2-phenylenediamine.

The substituted 1,2-phenylenediamine (1.01 g, 4.46 mmol) was thencyclized using phosphorous oxychloride (1.01 g, 6.6 mmol) as describedsupra to produce 2-(3-methylphenyl)benzimidazole.

The title compound was then produced by reacting the2-(3-methylphenyl)benzimidazole (0.75 g, 3.60 mmol) with 2-chlorobenzylchloride (0.50 ml, 4.19 mmol) essentially as described in Example 40,supra. MS 332, 334, mp 117° C.

Analysis for C₂₁ H₁₇ ClN₂ : Theory: C, 75.78; H, 5.15; N, 8.42. Found:C, 75.99; H, 5.24; N, 8.43.

The following compounds were synthesized essentially as described inExample 56 by reacting 2-(3-methylphenyl)benzimidazole with theappropriately substituted benzyl halide.

EXAMPLE 57

1-(3-Chlorobenzyl)-2-(3-methylphenyl)benzimidazole.

MS 332, 334, mp 90° C.

Analysis for C₂₁ H₁₇ ClN₂ : Theory: C, 75.78; H, 5.15; N, 8.42. Found:C, 75.51; H, 5.20; N, 8.56.

EXAMPLE 58

1-(4-Chlorobenzyl)-2-(3-methylphenyl)benzimidazole.

MS 332, 334, mp 108.5° C.

Analysis for C₂₁ H₁₇ ClN₂ : Theory: C, 75.78; H, 5.15; N, 8.42. Found:C, 75.55; H, 5.29; N, 8.37.

EXAMPLE 60

1-(2-Bromobenzyl)-2-(3-methylphenyl)benzimidazole.

MS 376, 378, mp 134° C.

Analysis for C₂₁ H₁₇ BrN₂ : Theory: C, 66.85; H, 4.54; N, 7.42. Found:C, 67.13; H, 4.60; N, 7.34.

EXAMPLE 61

1-(2-Iodobenzyl)-2-(3-methylphenyl)benzimidazole.

MS 424, 425, mp 129° C.

Analysis for C₂₁ H₁₇ IN₂ . 0.1 hexanes: Theory: C, 59.93; H, 4.28; N,6.47. Found: C, 60.20; H, 4.12; N, 6.87.

EXAMPLE 62

1-(2,6-Dichlorobenzyl)-2-(3-methylphenyl)benzimidazole.

mp 148° C., NMR, IR, MS 366, 368.

Analysis for C₂₁ H₁₆ Cl₂ N₂.0.1 hexanes: Theory: C, 69.02; H, 4.67; N,7.45. Found: C, 69.25; H, 4.42; N, 7.21.

EXAMPLE 63

1-(2,4-Dichlorobenzyl)-2-(3-methylphenyl)benzimidazole.

mp 161° C., MS 366, 368, IR, NMR.

Analysis for C₂₁ H₁₆ Cl₂ N₂ : Theory: C, 68.68; H, 4.39; N, 7.63. Found:C, 68.48; H, 4.61; N, 7.70.

EXAMPLE 64

1-(3,4-Dichlorobenzyl)-2-(3-methylphenyl)benzimidazole.

mp 85.5° C., MS 366, 368, IR, NMR.

Analysis for C₂₁ H₁₆ Cl₂ N₂ : Theory: C, 68.68; H, 4.39; N, 7.63. Found:C, 68.88; H, 4.41; N, 7.50.

EXAMPLE 65

1-(3-Methoxybenzyl)-2-(3-methylphenyl)benzimidazole.

Oil at room temperature. NMR, IR, MS 328.

Analysis for C₂₂ H₂₀ N₂ O: Theory: C, 80.46; H, 6.14; N, 8.53. Found: C,81.39; H, 6.70; N, 8.23.

EXAMPLE 66

1-(4-Methoxybenzyl)-2-(3-methylphenyl)benzimidazole.

mp 91° C., NMR, IR, MS 328.

Analysis for C₂₂ H₂₀ N₂ O: Theory: C, 80.46; H, 6.14; N, 8.53. Found: C,80.68; H, 6.31; N, 8.63.

EXAMPLE 67

Synthesis of 1-(3-hydroxybenzyl)-2-(3-methylphenyl)benzimidazolehydrobromide.

This compound was prepared by first synthesizing1-(3-methoxybenzyl)-2-(3-methylphenyl)benzimidazole as described inExample 65, supra. With an amount of the compound of Example 65 (4.31 g,13.12 mmol) in glacial acetic acid (50 ml) and hydrobromic acid (300 mlof a 48% w/v in acetic acid solution). This mixture was stirred for 2hours while warming to reflux. The mixture was then stirred at refluxfor about three hours.

The reaction mixture was then allowed to cool to room temperature afterwhich time the reaction mixture was partitioned between water (1 liter)and methylene chloride, followed by extraction with methylene chloride(3×500 ml). The organic fractions were combined and dried over magnesiumsulfate. After reducing the volume of the organic solvents in vacuo, theorganic fraction was washed with water (3×250 ml) to remove residualhydrobromic acid. The organic phases were combined and dried in vacuo toyield a gray solid which was washed with diethyl ether (2×250 ml) anddried in a vacuum oven. NMR, IR, MS 314, mp 235° C.

Analysis for C₂₁ H₁₈ N₂ O . HBr: Theory: C, 63.81; H, 4.84; N, 7.09.Found: C, 64.45; H, 5.02; N, 7.23.

EXAMPLE 69

Synthesis of1-benzyl-2-(3,4,5-trimethoxyphenyl)-6-(hydroxy)-benzimidazolehydrochloride.

The title compound was prepared by first reacting 4-amino-3-nitrophenol(25.0 g, 162.2 mmol) with 3,4,5-trimethoxybenzoyl chloride (112 g, 485.6mmol) in N,N-diethylaniline (69 ml) and toluene (500 ml). The reactionmixture was stirred and the temperature was raised to 100° C. Thesolution was maintained at this temperature for about 6 hours as ayellow precipitate formed. The reaction mixture was then partitionedbetween 1N hydrochloric acid (250 ml) and ethyl acetate (250 ml). Thecrystals were then removed by filtration and washed with ethyl acetate(300 ml) and water (300 ml) to yield the intermediate1-(3,4,5-trimethoxy)benzyl ester of4-(3,4,5-trimethoxyphenylcarbonylamino)-2-nitrophenol.

A benzyl group was then substituted on the nitro group by reacting theabove intermediate (10 g, 18.4 mmol) with benzaldehyde (6 ml) inN,N-dimethylformamide (100 ml) under a hydrogen atmosphere (60° C. at 60p.s.i.) with 6.0 g of a palladium on activated carbon catalyst.

The benzimidazole ring was closed using phosphorous oxychloride inchloroform as described supra. The ester on the 6-hydroxy group of thebenzimidazole was removed by incubating the intermediate in 1N sodiumhydroxide (500 ml) and tetrahydrofuran (500 ml). This solution wasstirred overnight, followed by acidification with a sufficient amount of1 N hydrochloric acid to reduce the pH to 1.0. This solution was thenwashed with ethyl acetate (2×500 ml). The organic fractions werecombined, dried over magnesium sulfate, and the solvents removed invacuo to yield a brownish/red solid. The title compound was furtherpurified by flash chromatography to yield a grayish solid. MS 390.

Analysis for C₂₃ H₂₂ N₂ O₄.HCl: Theory: C, 64.71; H, 5.43; N, 6.56.Found: C, 65.12; H, 5.40; N, 6.63.

EXAMPLE 70

Synthesis of1-benzyl-2-(3,4,5-trimethoxyphenyl)-6-[2-(4-morpholinyl)ethoxy]benzimidazole.

The title compound was prepared by reacting the compound of Example 69,supra, (0.23 g, 0.59 mmol) with 4-(2-chloroethyl)morpholinehydrochloride (1.10 g, 5.91 mmol) and potassium carbonate (1.63 g, 11.80mmol) in acetone. The reaction conditions employed were essentially asdescribed for previous alkylations. MS 503.

Analysis for C₂₉ H₃₃ N₃ O₅ : Theory: C, 69.17; H, 6.60; N, 8.34. Found:C, 69.10; H, 6.70; N, 8.42.

EXAMPLE 71

Synthesis of1-benzyl-2-(3,4,5-trimethoxyphenyl)-6-[2-(1-piperidinyl)ethoxy]benzimidazole.

The title compound was prepared essentially as described in Example 70except that 1-(2-chloroethyl)piperidine hydrochloride was employed inplace of 4-(2-chloroethyl)morpholine hydrochloride. MS 501.

Analysis for C₃₀ H₃₅ N₃ O₄ : Theory: C, 71.83; H, 7.03; N, 8,38. Found:C, 71.95; H, 7.27; N, 8.17.

EXAMPLE 72

Synthesis of1-benzyl-2-(3,4,5-trimethoxyphenyl)-6-[2-(1-pyrroldinyl)ethoxy]benzimidazole.

The title compound was prepared essentially as described in Example 70except that 1-(2-chloroethyl)pyrrolidine hydrochloride was employed inplace of 4-(2-chloroethyl)morpholine hydrochloride. MS 488.

Analysis for C₂₉ H₃₃ N₃ O₄ : Theory: C, 71.44; H, 6.82; N, 8.62. Found:C, 71.61; H, 7.05; N, 8.87.

EXAMPLE 73

Synthesis of1-benzyl-2-(3,4,5-trimethoxyphenyl)-6-[2-(1-hexamethyleneiminyl)ethoxy]benzimidazole.

The title compound was prepared essentially as described in Example 70except that 1-(2-chloroethyl)hexamethyleneimine hydrochloride wasemployed in place of 4-(2-chloroethyl)morpholine hydrochloride. NMR, IR,MS 515, mp 122.5° C.

Analysis for C₃₁ H₃₇ N₃ O₄ : Theory: C, 72.21; H, 7.23; N, 8.15. Found:C, 72.18; H, 7.19; N, 8.42.

EXAMPLE 74

Synthesis of1-benzyl-2-(3,4,5-trimethoxyphenyl)-6-[3-(1-piperidinyl)propoxy]benzimidazole.

The title compound was prepared essentially as described in Example 70except that 1-(3-chloropropyl)piperidine hydrochloride was employed inplace of 4-(2-chloroethyl)morpholine hydrochloride. mp 92° C., NMR, IR,MS 515.

Analysis for C₃₁ H₃₇ N₃ O₄ : Theory: C, 72.21; H, 7.23; N, 8.15. Found:C, 72.50; H, 7.26; N, 7.90.

EXAMPLE 75

Synthesis of1-benzyl-2-(3,4,5-trimethoxyphenyl)-6-(3-chloropropoxy)benzimidazole.

The title compound was prepared essentially as described in Example 70except that 1-chloro-3-iodopropane was employed in place of4-(2-chloroethyl)morpholine hydrochloride. mp 118.5° C., MS 466, 468,NMR, IR.

Analysis for C₂₆ H₂₇ ClN₂ O₄.0.5 H₂ O: Theory: C, 65.61; H, 5.93; N,5.89. Found: C, 65.92; H, 5.74; N, 5.91.

EXAMPLE 76

Synthesis of1-benzyl-2-(3,4,5-trimethoxyphenyl)-6-(2-chloroethoxy)benzimidazole.

The title compound was prepared essentially as described in Example 70except that 1-bromo-2-chloroethane was employed in place of4-(2-chloroethyl)morpholine hydrochloride. IR, NMR, MS 452, 454, mp 129°C.

Analysis for C₂₅ H₂₅ ClN₂ O₄ : Theory: C, 66.30; H, 5.56; N, 6.19.Found: C, 67.33; H, 5.41; N, 6.61.

EXAMPLE 77

Synthesis of1-benzyl-2-(3,4,5-trimethoxyphenyl)-6-[2-[4-(piperidin-1-yl)piperdin-1-yl]ethoxy]benzimidazole.

The title compound was prepared by reacting the compound of Example 76,supra, (0.45 g, 1.0 mmol) with 4-piperdin-1-yl)piperidine (2.0 g, 11.9mmol) in the presence of the base N,N-diisopropylethylamine,tetra-n-butylammonium iodide and acetonitrile at 80° C. After incubatingovernight at 80° C. the reaction was washed with water (2×500 ml),followed by a wash with a saturated sodium chloride solution (1×500 ml).The organic phase was then dried over potassium carbonate and thesolvents were removed in vacuo to yield a light brown oil. The desiredproduct was purified by chromatography and triturated with diethyl etherto yield a light brown powder, which was removed by filtration andwashed with diethyl ether to yield the purified title compound. MS 584,585, NMR, IR, mp 143° C.

Analysis for C₃₅ H₄₄ N₄ O₄ : Theory: C, 71.89; H, 7.58; N, 9.58. Found:C, 72.11; H, 7.62; N, 9.67.

EXAMPLE 78

Synthesis of1-benzyl-2-(3,4,5-trimethoxyphenyl)-6-[1-methyl-2-(N,N-dimethylamino)]ethoxy]benzimidazole.

The title compound was prepared by reacting the compound of Example 70,supra, 0.45 g, 1.15 mmol) with 1-methyl-2-dimethylaminoethyl chloride(1.82 g, 11.51 mmol) and potassium chloride (3.18 g, 23.01 mmol) in 100ml of acetone. The reactants were admixed and then heated to refluxovernight.

After the overnight incubation the reaction mixture was acidified byadding 500 ml of 1N hydrochloric acid and then washed with ethyl acetate(2×250 ml). The aqueous layer was then basified and extracted with ethylacetate (500 ml). The organic fractions were combined and washed with asaturated sodium chloride solution and dried over potassium carbonate.The solvents were removed in vacuo to yield a yellow oil which wastriturated with hexanes, forming a white solid. This was furtherpurified by crystallizing from 10:1 hexanes:ethanol to yield the desiredtitle product. IR, NMR, MS 475, 476, mp 93° C.

Analysis for C₂₈ H₃₃ N₃ O₄ : Theory: C, 70.71; H, 6.99; N, 8.84. Found:C, 70.93; H, 7.01; N, 8.92.

EXAMPLE 79

Synthesis of1-benzyl-2-(3,4,5-trimethoxyphenyl)-6-[2-(N,N-dimethylamino)ethoxy]benzimidazole.

The title compound was prepared essentially as described in Example 78,supra, except that 2-dimethylaminoethyl chloride was employed in placeof the 1-methyl-2-dimethylaminoethyl chloride. IR, NMR, MS 461, mp 108°C.

Analysis for C₂₇ H₃₁ N₃ O₄.0.1 hexanes: Theory: C, 70.51; H, 6.95; N,8.94. Found: C, 70.98; H, 6.60; N, 8.62.

EXAMPLE 80

Synthesis of1-benzyl-2-(3,4,5-trimethoxyphenyl)-6-[3-(N,N-dimethylamino)propoxy]benzimidazole.

The title compound was prepared essentially as described in Example 78,supra, except that 3-dimethylaminopropyl chloride was employed in placeof the 1-methyl-2-dimethylaminoethyl chloride. IR, NMR, MS 475, mp 112°C.

Analysis for C₂₈ H₃₃ N₃ O₄ : Theory: C, 70.71; H, 6.99; N, 8.83. Found:C, 70.42; H, 6.97; N, 8.68.

EXAMPLE 81

Synthesis of1-benzyl-2-(3,4,5-trimethoxyphenyl)-6-[2-(N,N-diisopropylamino)ethoxy]benzimidazole.

The title compound was prepared essentially as described in Example 78,supra, except that 2-diisopropylaminoethyl chloride was employed inplace of the 1-methyl-2-dimethylaminoethyl chloride. IR, NMR, MS 517,518, mp 101° C.

Analysis for C₃₁ H₃₉ N₃ O₄ : Theory: C, 71.93; H, 7.59; N, 8.12. Found:C, 71.91; H, 7.76; N, 7.98.

EXAMPLE 83

Synthesis of1-benzyl-2-(3,4,5-trimethoxyphenyl)-6-[2-(4-methyl-1-piperazinyl)ethoxy]benzimidazole.

The title compound was prepared essentially as described in Example 77,supra, employing the compound of Example 76, except that1-methylpiperazine was employed in place of the4-(piperdin-1-yl)piperidine. IR, NMR, MS 517, mp 113° C.

Analysis for C₃₀ H₃₆ N₄ O₄.0.5 H₂ O: Theory: C, 68.55; H, 7.09; N,10.66. Found: C, 68.83; H, 7.19; N, 10.98.

EXAMPLE 84

Synthesis of 1-benzyl-2-(3-methylphenyl)-6-hydroxybenzimidazole

The title compound was prepared essentially as described in Example 69,supra, except that 3-methylbenzoyl chloride (18.8 g, 121.6 mmol) wasemployed instead of the 3,4,5-trimethoxybenzoyl chloride. MS 314

Analysis for C₂₁ H₁₈ N₂ O: Theory: C, 80.23; H, 5.77; N, 8.91. Found: C,80.10; H, 5.85; N, 8.81.

EXAMPLE 85

Synthesis of1-benzyl-2-(3-methylphenyl)-6-[2-(1-piperidinyl)ethoxy]benzimidazole

The title compound was synthesized by reacting the compound of Example84, supra, (0.25 g, 0.79 mmol) with 2-(piperdinyl-1-yl)ethyl chloride(17.46 g, 7.9 mmol) in the presence of potassium carbonate (2.20 g, 15.9mmol) and acetone (150 ml). These contents were added to a flask andrefluxed overnight.

After the overnight incubation, the reaction mixture was quenched byadding 0.5 N hydrochloric acid (300 ml) and was washed with ethylacetate (300 ml). The aqueous layer was basified with 1N sodiumhydroxide until the pH=10. This aqueous layer was extracted with ethylacetate (300 ml). The organic fractions were combined and the solventvolume was reduced in vacuo, leaving a yellow oil. Diethyl ether andhexanes were added to this oil and it was then placed at -20° C. untilcrystals of the title product formed, which were then harvested byfiltration. MS 425, 426.

Analysis for C₂₈ H₃₁ N₃ O: Theory: C, 79.03; H, 7.34; N, 9.87. Found: C,78.75; H, 7.47; N, 10.09.

EXAMPLE 86

Synthesis of1-benzyl-2-(3-methylphenyl)-6-[2-(1-pyrrolidinyl)ethoxy]benzimidazole.

The title product was prepared essentially as described in Example 85,supra, except that 1-(2-chloroethyl)pyrrolidine hydrochloride wasemployed instead of the 2-(piperdinyl-1-yl)ethyl chloride. MS 411.

Analysis for C₂₇ H₂₉ N₃ O: Theory: C, 78.80; H, 7.10; N, 10.21. Found:C, 78.85; H, 7.14; N, 10.08.

EXAMPLE 87

Synthesis of1-benzyl-2-(3-methylphenyl)-6-[2-(4-morpholinyl)ethoxy]benzimidazole

The title product was prepared essentially as described in Example 85,supra, except that 4-(2-chloroethyl)morpholine hydrochloride wasemployed instead of the 2-(piperdinyl-1-yl)ethyl chloride. MS 427.

Analysis for C₂₇ H₂₉ N₃ O₂ : Theory: C, 75.85; H, 6.84; N, 9.83. Found:C, 75.75; H, 6.89; N, 9.88.

EXAMPLE 88

Synthesis of1-benzyl-2-(3-methylphenyl)-6-[2-(N,N-dimethylamino)ethoxy]benzimidazole

The title product was prepared essentially as described in Example 85,supra, except that 2-(N,N-dimethylamino)ethyl chloride was employedinstead of the 2-(piperdinyl-1-yl)ethyl chloride. MS 385.

Analysis for C₂₅ H₂₇ N₃ O: Theory: C, 77.89; H, 7.06; N, 10.90. Found:C, 77.88; H, 7.14; N, 10.74.

EXAMPLE 89

Synthesis of1-benzyl-2-(3-methylphenyl)-6-[2-(N,N-dibenzylamino)ethoxy]benzimidazole

The title product was prepared essentially as described in Example 85,supra, except that 2-(N,N-dibenzylamino)ethyl chloride was employedinstead of the 2-(piperdinyl-1-yl)ethyl chloride. MS 537.

Analysis for C₃₇ H₃₅ N₃ O: Theory: C, 82.65; H, 6.56; N, 7.82. Found: C,82.47; H, 6.73; N, 7.81.

EXAMPLE 90

Synthesis of1-benzyl-2-(3-methylphenyl)-6-[2-(N-phenyl-N-ethylamino)ethoxy]benzimidazole

The title product was prepared essentially as described in Example 85,supra, except that 2-(N-benzyl-N-ethylamino)ethyl chloride was employedinstead of the 2-(piperdinyl-1-yl)ethyl chloride. Ms 461, 462.

Analysis for C₃₁ H₃₁ N₃ O: Theory: C, 80.66; H, 6.77; N, 9.10. Found. C,80.37; H, 6.81; N, 8.98.

EXAMPLE 91

Synthesis of1-benzyl-2-(3-methylphenyl)-6-[2-(N,N-isopropylamino)ethoxy]benzimidazole

The title product was prepared essentially as described in Example 85,supra, except that 2-(N,N-diisopropylamino)ethyl chloride was employedinstead of the 2-(piperdinyl-1-yl)ethyl chloride. MS 441.

Analysis for C₂₉ H₃₅ N₃ O: Theory: C, 78.87; H, 7.99; N, 5.51. Found: C,79.07; H, 8.12; N, 5.60.

EXAMPLE 92

Synthesis of1-benzyl-2-(3-methylphenyl)-6-[2-(hexamethyleneimin-1-yl)ethoxy]benzimidazole

The title product was prepared essentially as described in Example 85,supra, except that 2-(hexamethyleneimin-1-yl)ethyl chloride was employedinstead of the 2-(piperdinyl-1-yl)ethyl chloride. MS 439.

Analysis for C₂₉ H₃₃ N₃ O: Theory: C, 79.23; H, 7.57; N, 9.56. Found: C,79.45; H, 7.72; N, 9.66.

EXAMPLE 93

Synthesis of1-benzyl-2-(3-methylphenyl)-6-[2-(N,N-diethylamino)ethoxy]-benzimidazole

The title product was prepared essentially as described in Example 85,supra, except that 2-(N,N-diethylamino)ethyl chloride was employedinstead of the 2-(piperdinyl-1-yl)ethyl chloride. MS 413, 414.

Analysis for C₂₇ H₃₁ N₃ O . 0.25 H₂ O: Theory: C, 77.57; H, 7.59; N,10.05. Found: C, 77.60; H, 7.42; N, 9.74.

EXAMPLE 94

Synthesis of1-benzyl-2-(3-methylphenyl)-6-[3-(N,N-dimethylamino)propoxy]benzimidazole

The title product was prepared essentially as described in Example 85,supra, except that 3-(N,N-dimethylamino)propyl chloride was employedinstead of the 2-(piperdinyl-1-yl)ethyl chloride. MS 399.

Analysis for C₂₆ H₂₉ N₃ O: Theory: C, 78.16; H, 7.32; N, 10.52. Found:C, 77.93; H, 7.32; N, 10.25.

EXAMPLE 95

Synthesis of1-benzyl-2-(3-methylphenyl)-6-[3-(piperdin-1-yl)propoxy]-benzimidazole.

The title product was prepared essentially as described in Example 85,supra, except that 3-(piperidin-1-yl)propyl chloride was employedinstead of the 2-(piperdinyl-1-yl)ethyl chloride. mp 84° C., MS 439,NMR, IR.

Analysis for C₂₉ H₃₃ N₃ O: Theory: C, 79.23; H, 7.57; N, 9.55. Found: C,79.39; H, 7.59; N, 9.59.

EXAMPLE 96

Synthesis of1-benzyl-2-(3-methylphenyl)-6-[2-(N,N-dimethylamino)propoxy]-benzimidazole

The title product was prepared essentially as described in Example 85,supra, except that 2-(N,N-dimethylamino)propyl chloride was employedinstead of the 2-(piperdinyl- 1-yl)ethyl chloride. mp 74° C., NMR, IR,MS 399, 400.

Analysis for C₂₆ H₂₉ N₃ O: Theory: C, 78.16; H, 7.32; N, 10.52. Found:C, 79.58; H, 7.44; N, 10.49.

EXAMPLE 97

Synthesis of1-benzyl-2-(3-methylphenyl)-6-(3-chloropropoxy)-benzimidazole

The title product was prepared essentially as described in Example 85,supra, except that 3-chloropropyl iodide was employed instead of the2-(piperdinyl-1-yl)ethyl chloride. mp 97° C., NMR, IR, MS 390, 391.

Analysis for C₂₄ H₂₃ ClN₂ O: Theory: C, 73.74; H, 5.93; N, 7.17. Found:C, 73.61; H, 5.94; N, 7.39.

EXAMPLE 98

Synthesis of1-benzyl-2-(3-methylphenyl)-6-(2-chloroethoxy)-benzimidazole

The title product was prepared essentially as described in Example 85,supra, except that 2-chloroethyl bromide was employed instead of the2-(piperdinyl-1-yl)ethyl chloride. mp 88° C., MS 376, 378, NMR, IR.

Analysis for C₂₃ H₂₁ ClN₂ O: Theory: C, 73.30; H, 5.62; N, 7.43. Found:C, 73.04; H, 5.67; N, 7.65.

EXAMPLE 99

Synthesis of1-benzyl-2-(3-methylphenyl)-6-[3-(morpholin-4-yl)propoxy)benzimidazole.

The title compound was prepared by first adding morpholine (1.02 g,11.77 mmol) and the compound of Example 97, supra, (0.39 g, 1.00 mmol)to 125 ml of acetonitrile while stirring under nitrogen purge. To thismixture is then added diisopropylethyl aniline (1.51 ml, 8.67 mmol)dropwise. This reaction mixture is then allowed to stir overnight.

After the overnight stirring, additional diisopropyl aniline (1.00 ml)is added and the mixture is then heated to 60° C. and maintained at thistemperature for about 3 days. The reaction mixture was then washed withwater (3×250 ml) and the solvents were removed in vacuo, resulting in ayellow oil.

The yellow oil was further purified by chromatography using ethylacetate, followed by removal of the solvents in vacuo, and triturationwith hexanes to afford yellow crystals. NMR, MS 441, IR, mp 120° C.

Analysis for C₂₈ H₃₁ N₃ O₂ : Theory: C, 76.16; H, 7.08; N, 9.52. Found:C, 76.39; H, 7.26; N, 9.54.

EXAMPLE 100

Synthesis of1-benzyl-2-(3-methylphenyl)-6-[3-(pyrrolidin-1-yl)propoxy)benzimidazole

The title compound was prepared essentially as described in Example 99,supra, except that pyrrolidine was employed in place of morpholine. mp120° C., NMR, IR, MS 425.

Analysis for C₂₈ H₃₁ N₃ O: Theory: C, 79.03; H, 7.34; N, 9.87. Found: C,79.22; H, 7.39; N, 9.83.

EXAMPLE 101

Synthesis of1-benzyl-2-(3-methylphenyl)-6-[3-hexamethyleneimin-1-yl)propoxy)benzimidazole

The title compound was prepared essentially as described in Example 99,supra, except that hexamethyleneimine was employed in place ofmorpholine. mp 69.5° C., NMR, IR, MS 453, 454.

Analysis for C₃₀ H₃₅ N₃ O: Theory: C, 79.43; H, 7.78; N, 9.26. Found: C,79.60; H, 7.88; N, 9.28.

EXAMPLE 102

Synthesis of1-benzyl-2-(3-methylphenyl)-6-[3-(heptamethyleneimin-1-yl)propoxy)benzimidazole

The title compound was by reacting the compound of Example 97, supra,(0.39 g, 1.00 mmol) with heptamethyleneimine (10 g, 88.3 mmol) in thepresence of N,N-diisopropylethylamine (2 ml) and acetonitrile (5 ml).This reaction mixture was raised to 80° C. and allowed to stir at thattemperature overnight. The compound was purified essentially asdescribed in Example 99, supra. NMR, MS 467, mp 77° C.

Analysis for C₃₁ H₃₇ N₃ O: Theory: C, 79.62; H, 7.97; N, 8.98. Found: C,79.50; H, 7.99; N, 8.99.

EXAMPLE 103

Synthesis of1-benzyl-2-(3-methylphenyl)-6-[2-(4-methyl-piperazin-1-yl)ethoxy]benzimidazole

The title compound was prepared by reacting the compound of Example 98,supra, (1.89 g, 5.01 mmol) with 1-methyl-piperazine (65 ml) in thepresence of N,N-diisopropylethyl amine (4 ml) and N,N-dimethylformamide(100 ml) under nitrogen atmosphere. This reaction mixture was heated to50° C. and stirred overnight at that temperature. The compound waspurified essentially as described in Example 99, supra. NMR, IR, MS 440,441, mp 91° C.

Analysis for C₂₈ H₃₂ N₄ O: Theory: C, 76.33; H, 7.32; N, 12.72. Found:C, 76.19; H, 7.15; N, 12.96.

EXAMPLE 104

Synthesis of1-(2-trifluoromethylbenzyl)-2-(3,4,5-trimethoxyphenyl)-6-hydroxybenzimidazole

The title compound was prepared by first reacting3,4,5-trimethoxybenzoyl chloride (112.0 g, 485.6 mmol) with4-amino-3-nitrophenol (25.0 g, 162.2 mmol) in N,N-diethylaniline (69 ml)and toluene (500 ml). This reaction mixture was heated to 100° C. andmaintained at that temperature for about 6 hours. The intermediate esterof 4-(3,4,5-trimethoxyphenylcarbonylamino)-3-nitrophenol was purifiedessentially as described in Example 69, supra.

The nitro moiety of the above-described intermediate was reduced to anamino group by catalytic hydrogenation using a palladium on activatedcarbon catalyst as described previously. This primary amino group wasthen alkylated by reacting with 2-trifluoromethylbenzyl bromide in thepresence of N,N-diisopropylethyl amine and tetrahydrofuran. This mixturewas allowed to reflux overnight.

The reaction mixture was then washed with water (5×500 ml) followed by awash with saturated sodium chloride (500 ml). The organic phase wasdried over potassium carbonate, and the solvents were removed in vacuo,leaving a brown solid. Following trituration in diethyl ether a graysolid formed.

The benzimidazole ring was dosed using phosphorous oxychloride inchloroform as previously described. The protecting ester on the6-hydroxy of the benzimidazole ring was removed by incubating theprotected compound in 1N sodium hydroxide in tetrahydrofuran to cleavethis group, leaving the title compound. NMR, IR, MS 458, mp 191° C.

Analysis for C₂₄ H₂₁ F₃ N₂ O₄ : Theory: C, 62.88; H, 4.62; N, 6.11.Found: C, 62.89; H, 4.88; N, 5.90.

EXAMPLE 105

Synthesis of1-(2-trifluoromethylbenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2-(piperidin-1-yl)ethoxy]benzimidazole

The title compound was prepared by reacting the compound of Example 104with 1-(2-chloroethyl)piperidine hydrochloride essentially as previouslydescribed. mp 167° C., NMR, IR, MS 570.

Analysis for C₃₁ H₃₄ F₃ N₃ O₄ : Theory: C, 65.37; H, 6.02; N, 7.38.Found: C, 65.40; H, 6.02; N, 7.41.

EXAMPLE 106

Synthesis of1-(2-trifluoromethylbenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2-(N,N-dimethylamino)propoxy]-benzimidazole

The title compound was prepared by reacting the compound of Example 104with 2-(N,N-dimethylamino)propyl chloride essentially as previouslydescribed. mp 163° C., NMR, IR, MS 543, 544.

Analysis for C₂₉ H₃₂ F₃ N₃ O₄ : Theory: C, 64.08; H, 5.93; N, 7.73.Found: C, 64.00; H, 5.86; N, 7.68.

EXAMPLE 107

Synthesis of1-(2-trifluoromethylbenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2-(N,N-dimethylamino)ethoxy]-benzimidazole

The title compound was prepared by reacting the compound of Example 104with 2-(N,N-dimethylamino)ethyl chloride essentially as previouslydescribed. mp 151° C., NMR, IR, MS 529.

Analysis for C₂₈ H₃₀ F₃ N₃ O₄ : Theory: C, 63.51; H, 5.71; N, 7.94.Found: C, 63.79; H, 5.57; N, 8.02.

EXAMPLE 108

Synthesis of1-(2-trifluoromethylbenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[3-(N,N-dimethylamino)propoxy]-benzimidazole

The title compound was prepared by reacting the compound of Example 104with 3-(N,N-dimethylamino)propyl chloride essentially as previouslydescribed. mp 142° C., NMR, IR, MS 543.

Analysis for C₂₉ H₃₂ F₃ N₃ O₄ : Theory: C, 64.08; H, 5.93; N, 7.73.Found: C, 64.33; H, 5.78; N, 7.47.

EXAMPLE 109

Synthesis of1-(2-trifluoromethylbenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[3-(piperidin-1-yl)propoxy]benzimidazole

The title compound was prepared by reacting the compound of Example 104with 3-(piperidin-1-yl)propyl chloride essentially as previouslydescribed mp 138° C., IR, NMR, MS. 584

Analysis for C₃₂ H₃₆ F₃ N₃ O₄ : Theory: C, 65.85; H, 6.22; N, 7.20.Found: C, 65.74; H, 6.07; N, 7.35.

EXAMPLE 110

Synthesis of1-(2-trifluoromethylbenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2-(hexamethyleneimin-1-yl)ethoxy]benzimidazole

The title compound was prepared by reacting the compound of Example 104with 2-(hexamethyleneimin-1-yl)ethyl chloride essentially as previouslydescribed. mp 156° C., IR, NMR, MS 583, 584.

Analysis for C₃₂ H₃₆ F₃ N₃ O₄ : Theory: C, 65.85; H, 6.22; N, 7.20.Found: C, 65.59; H, 5.98; N, 7.33.

EXAMPLE 111

Synthesis of1-(2-trifluoromethylbenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2-(pyrrolidin-1-yl)ethoxy]benzimidazole

The title compound was prepared by reacting the compound of Example 104with 2-(pyrrolidin-1-yl)ethyl chloride essentially as previouslydescribed. mp 143° C., NMR, IR, MS 555.

Analysis for C₃₀ H₃₂ F₃ N₃ O₄ : Theory: C, 64.85; H, 5.80; N, 7.56.Found: C, 64.93; H, 5.87; N, 7.54.

EXAMPLE 112

Synthesis of1-(2-trifluoromethylbenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2-(morpholin-4-yl)ethoxy]benzimidazole

The title compound was prepared by reacting the compound of Example 104with 2-(morpholin-4-yl)ethyl chloride essentially as previouslydescribed. mp 175° C., NMR, IR, MS 572.

Analysis for C₃₀ H₃₂ F₃ N₃ O₅ : Theory: C, 63.04; H, 5.64; N, 7.35.Found: C, 62.82; H, 5.74; N, 7.38.

EXAMPLE 113

Synthesis of1-(2-trifluoromethylbenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2-(N,N-diisopropylamino)ethoxy]-benzimidazole

The title compound was prepared by reacting the compound of Example 104with 2-(N,N-diisopropylamino)ethyl chloride essentially as previouslydescribed. mp 184° C., MS 585, NMR, IR.

Analysis for C₃₂ H₃₈ F₃ N₃ O₄ : Theory: C, 65.63; H, 6.54; N, 7.18.Found: C, 65.67; H, 6.42; N, 7.35.

EXAMPLE 114

Synthesis of1-(2-bromobenzyl)-2-(3,4,5-trimethoxyphenyl)-6-hydroxybenzimidazole

The title compound was prepared essentially as described in Example 104except that 2-bromobenzyl bromide was employed in place of2-trifluoromethylbenzyl bromide. mp 208° C., NMR, IR, MS 468, 470.

Analysis for C₂₃ H₂₁ BrN₂ O₄ : Theory: C, 58.86; H, 4.51; N, 5.97.Found: C, 58.61; H, 4.81; N, 6.12.

EXAMPLE 115

Synthesis of1-(2-bromobenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2-(piperidin-1-yl)ethoxy]benzimidazole

The title compound was prepared by reacting the compound of Example 114with 2-(piperidin-1-yl)ethyl chloride essentially as previouslydescribed mp 145° C., NMR, MS 579, 581, IR.

Analysis for C₃₀ H₃₄ BrN₃ O₄ : Theory: C, 62.07; H, 5.90; N, 7.24.Found: C, 61.86; H, 5.91; N, 7.08.

EXAMPLE 116

Synthesis of1-(2-bromobenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2-(N,N-dimethylamino)propoxy]benzimidazole

The title compound was prepared by reacting the compound of Example 114with 2-(N,N-dimethylamino)propyl chloride essentially as previouslydescribed. mp 152° C., NMR, IR, MS 553, 555.

Analysis for C₂₈ H₃₂ BrN₃ O₄ : Theory: C, 60.65; H, 5.82; N, 7.58.Found: C, 60.85; H, 5.77; N, 7.44.

EXAMPLE 117

Synthesis of1-(2-bromobenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2-(N,N-dimethylamino)ethoxy]benzimidazole

The title compound was prepared by reacting the compound of Example 114with 2-(N,N-dimethylamino)ethyl chloride essentially as previouslydescribed. mp 152° C., NMR, IR, MS 539, 541.

Analysis for C₂₇ H₃₀ BrN₃ O₄ : Theory: C, 60.00; H, 5.59; N, 7.77.Found: C, 59.83; H, 5.63; N, 7.54.

EXAMPLE 118

Synthesis of1-(2-bromobenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[3-(N,N-dimethylamino)propoxy]benzimidazole

The title compound was prepared by reacting the compound of Example 114with 3-(N,N-dimethylamino)propyl chloride essentially as previouslydescribed mp 141° C., NMR, IR, MS 553, 555.

Analysis for C₂₈ H₃₂ BrN₃ O₄ : Theory: C, 60.65; H, 5.82; N, 7.58.Found: C, 60.49; H, 6.03; N, 7.34.

EXAMPLE 119

Synthesis of1-(2-bromobenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2-(N,N-diisopropylamino)ethoxy]benzimidazole

The title compound was prepared by reacting the compound of Example 114with 2-(N,N-diisopropylamino)ethyl chloride essentially as previouslydescribed MS 595, 597.

Analysis for C₃₁ H₃₈ BrN₃ O₄ : Theory: C, 62.41; H, 6.42; N, 7.04.Found: C, 62.48; H, 6.48; N, 7.03.

EXAMPLE 120

Synthesis of1-(2-trifluoromethylbenzyl)-2-(3-methylphenyl)-6-hydroxybenzimidazole

The title compound was prepared essentially as described in Example 104,supra, except that 3-methylbenzoyl chloride was employed instead of3,4,5-trimethoxybenzoyl chloride. mp 233° C., MS 382, IR, NMR.

Analysis for C₂₂ H₁₇ F₃ N₂ O: Theory: C, 69.10; H, 4.48; N, 7.33. Found.C, 69.40; H, 4.49; N, 7.27.

EXAMPLE 121

Synthesis of1-(2-trifluoromethylbenzyl)-2-(3-methylphenyl)-6-[2-(piperidinyl-1-yl)ethoxy]benzimidazole

The title compound was prepared essentially as described in Example 105except that the compound of Example 120 was reacted with2-(piperidin-1-yl)ethyl chloride. mp 114° C., NMR, IR, MS 493.

Analysis for C₂₉ H₃₀ F₃ N₃ O: Theory: C, 70.57; H, 6.13; N, 8.51. Found:C, 70.77; H, 6.22; N, 8.50.

EXAMPLE 122

Synthesis of1-(2-trifluoromethylbenzyl)-2-(3-methylphenyl)-6-[2-(N,N-dimethylamino)ethoxy]benzimidazole

The title compound was prepared essentially as described in Example 107except that the compound of Example 120 was reacted with2-(N,N-dimethylamino)ethyl chloride. mp 93° C., NMR, IR, MS 453.

Analysis for C₂₆ H₂₆ F₃ N₃ O: Theory: C, 68.86; H, 5.78; N, 9.26. Found:C, 69.12; H, 5.79; N, 9.34.

EXAMPLE 123

Synthesis of1-(2-trifluoromethylbenzyl)-2-(3-methylphenyl)-6-[2-(N,N-diisopropylamino)ethoxy]-benzimidazole

The title compound was prepared essentially as described in Example 113except that the compound of Example 120 was reacted with2-(N,N-diisopropylamino)ethyl chloride. MS 510.

Analysis for C₃₀ H₃₄ F₃ N₃ O: Theory: C, 70.71; H, 6.72; N, 8.25. Found:C, 70.48; H, 6.59; N, 8.26.

EXAMPLE 124

Synthesis of1-(2-trifluoromethylbenzyl)-2-(3-methylphenyl)-6-[3-(N,N-dimethylamino)propoxy]benzimidazole

The title compound was prepared essentially as described in Example 106except that the compound of Example 120 was reacted with3-(N,N-dimethylamino)propyl chloride. mp 74° C., NMR, IR, MS 468.

Analysis for C₂₇ H₂₈ F₃ N₃ O: Theory: C, 69.36; H, 6.04; N, 8.99. Found:C, 69.52; H, 6.10; N, 9.03.

EXAMPLE 125

Synthesis of1-(2-trifluoromethylbenzyl)-2-(3-methylphenyl)-6-[1-methyl-2-(N,N-dimethylamino)ethoxy]-benzimidazole

The title compound was prepared essentially as described above exceptthat the compound of Example 120 was reacted with1-methyl-2-(N,N-dimethylamino)ethyl chloride, yielding the title productas an oil.

EXAMPLE 126

Synthesis of 1-(2-bromobenzyl)-2-(3-methylphenyl)-6-hydroxybenzimidazole

The title compound was prepared essentially as described in Example 114,supra, except that 3-methylbenzoyl chloride was employed instead of3,4,5-trimethoxybenzoyl chloride. mp 218° C., NMR, IR, MS 392, 394.

Analysis for C₂₁ H₁₇ BrN₂ O: Theory: C, 64.13; H, 4.36; N, 7.12. Found:C, 64.23; H, 4.51; N, 6.93.

EXAMPLE 127

Synthesis of1-(2-bromobenzyl)-2-(3-methylphenyl)-6-[2-(piperidinyl-1-yl)ethoxy]benzimidazole

The title compound was prepared essentially as described in Example 115except that the compound of Example 126 was reacted with2-(piperidin-1-yl)ethyl chloride. mp 107° C., NMR, IR, MS 503, 505.

Analysis for C₂₈ H₃₀ BrN₃ O: Theory: C, 66.67; H, 5.99; N, 8.33. Found:C, 66.97; H, 6.12; N, 8.19.

EXAMPLE 128

Synthesis of1-(2-bromobenzyl)-2-(3-methylphenyl)-6-[2-(N,N-dimethylamino)ethoxy]benzimidazole

The title compound was prepared essentially as described in Example 117except that the compound of Example 126 was reacted with2-(N,N-dimethylamino)ethyl chloride. mp 71° C., NMR, IR, MS 464, 466.

Analysis for C₂₅ H₂₆ BrN₃ O: Theory: C, 64.66; H, 5.64; N, 9.05. Found:C, 64.58; H, 5.58; N, 9.04.

EXAMPLE 130

Synthesis of1-(2-bromobenzyl)-2-(3-methylphenyl)-6-[3-(N,N-dimethylamino)propoxy]benzimidazole

The title compound was prepared essentially as described in Example 116except that the compound of Example 126 was reacted with3-(N,N-dimethylamino)propyl chloride. MS 479.

Analysis for C₂₆ H₂₈ BrN₃ O: Theory: C, 65.27; H, 5.90; N, 8.78. Found:C, 64.99; H, 5.85; N, 8.66.

EXAMPLE 131

Synthesis of1-(2-bromobenzyl)-2-(3-methylphenyl)-6-[1-methyl-2-(N,N-dimethylamino)ethoxy]benzimidazole

The title compound was prepared essentially as described above exceptthat the compound of Example 126 was reacted with1-methyl-2-(N,N-dimethylamino)ethyl chloride.

EXAMPLE 132

Synthesis of1-(2-trifluoromethylbenzyl)-2-(3,4-dimethylphenyl)-6-hydroxybenzimidazole

The title compound was prepared essentially as described in Example 104except that 3,4,dimethylbenzoyl chloride was employed instead of3,4,5-trimethoxybenzoyl chloride. mp 178° C., NMR, IR, MS 396.

Analysis for C₂₃ H₁₉ F₃ N₂ O: Theory: C, 69.69; H, 4.83; N, 7.07. Found:C, 69.40; H, 4.87; N, 6.90.

The following compounds were prepared essentially as described supra,except that the compound of Example 132 was employed as a startingmaterial.

EXAMPLE 133

1-(2-trifluoromethylbenzyl)-2-(3,4-dimethylphenyl)-6-[2-(piperidin-1-yl)ethoxy]benzimidazole.mp 131° C., NMR, MS 507, IR.

Analysis for C₃₀ H₃₂ F₃ N₃ O: Theory: C, 70.99; H, 6.35; N, 8.28. Found:C, 70.70; H, 6.23; N, 8.42.

EXAMPLE 134

1-(2-trifluoromethylbenzyl)-2-(3,4-dimethylphenyl)-6-[2-(N,N-dimethylamino)ethoxy]benzimidazole.mp 87° C., MS 467, NMR, IR.

Analysis for C₂₇ H₂₈ F₃ N₃ O: Theory: C, 69.36; H, 6.04; N, 8.99. Found:C, 69.42; H, 6.01; N, 8.91.

EXAMPLE 135

1-(2-trifluoromethylbenzyl)-2-(3,4-dimethylphenyl)-6-[2-(N,N-diisopropylamino)ethoxy]benzimidazole.mp 121° C., NMR, IR, MS 524.

Analysis for C₃₁ H₃₆ F₃ N₃ O: Theory: C, 71.11; H, 6.93; N, 8.03. Found:C, 71.34; H, 6.96; N, 8.26.

EXAMPLE 136

1-(2-trifluoromethylbenzyl)-2-(3,4-dimethylphenyl)-6-[2-(N,N-dimethylamino)propoxy]benzimidazole.

MS 481.

Analysis for C₂₈ H₃₀ F₃ N₃ O: Theory: C, 69.84; H, 6.28; N, 8.73. Found:C, 70.24; H, 6.33; N, 8.55.

EXAMPLE 136A

1-(2-trifluoromethylbenzyl)-2-(3,4-dimethylphenyl)-6-[1-methyl-2-(N,N-dimethylamino)ethoxy]benzimidazole

MS 481.

Analysis for C₂₈ H₃₀ F₃ N₃ O: Theory: C, 69.84; H, 6.28; N, 8.73. Found:C, 69.61; H, 6.35; N, 8.50.

EXAMPLE 137

1-(2-bromomethylbenzyl)-2-(3,4-dimethylphenyl)-6-hydroxybenzimidazole

The title compound was prepared essentially as described in Example 114,supra, except that 3,4-dimethylbenzoyl chloride was employed instead of3,4,5-trimethoxybenzoyl chloride. mp 213° C., MS 406, 408, NMR, IR.

Analysis for C₂₂ H₁₉ BrN₂ O: Theory: C, 64.56; H, 5.17; N, 6.84. Found:C, 64.76; H, 4.95; N, 6.62.

The following compounds were prepared essentially as described supra,except that the compound of Example 138 was employed as a startingmaterial.

EXAMPLE 138

1-(2-trifluoromethylbenzyl)-2-(3,4-dimethylphenyl)-6-[3-(N,N-dimethylamino)propoxy]benzimidazole

Analysis for C₂₇ H₃₀ BrN₃ O: Theory: C, 65.85; H, 6.14; N, 8.53. Found:C, 66.12; H, 6.20; N, 8.49.

EXAMPLE 139

1-(2-bromobenzyl)-2-(3,4-dimethylphenyl)-6-[2-(piperidin-1-yl)ethoxy]benzimidazole.mp 137° C., NMR, IR, MS 517, 519.

Analysis for C₂₉ H₃₂ BrN₃ O: Theory: C, 67.18; H, 6.72; N, 8.10. Found:C, 67.45; H, 6.30; N, 8.01.

EXAMPLE 140

1-(2-bromobenzyl)-2-(3,4-dimethylphenyl)-6-[2-(N,N-dimethylamino)ethoxy]benzimidazole.mp 102° C., IR, NMR, MS 478, 479, 480.

Analysis for C₂₆ H₂₈ BrN₃ O: Theory: C, 65.27; H, 5.90; N, 8.78. Found:C, 65.43; H, 5.88; N, 8.75.

EXAMPLE 141

1-(2-bromobenzyl)-2-(3,4-dimethylphenyl)-6-[2-(N,N-diisopropylamino)ethoxy]benzimidazole

MS 533, 535.

Analysis for C₃₀ H₃₆ BrN₃ O: Theory: C, 67.41; H, 6.79; N, 7.86. Found:C, 67.36; H, 6.60; N, 7.93.

EXAMPLE 142

1-(2-bromobenzyl)-2-(3,4-dimethylphenyl)-6-[2-(N,N-dimethylamino)propoxy]benzimidazole.MS 491, 493.

Analysis for C₂₇ H₃₀ BrN₃ O: Theory: C, 65.85; H, 6.14; N, 8.53. Found:C, 66.07; H, 6.18; N, 8.54.

EXAMPLE 142A

1-(2-bromobenzyl)-2-(3,4-dimethylphenyl)-6-[l-methyl-2-(N,N-dimethylamino)ethoxy]benzimidazole.MS 491, 493.

Analysis for C₂₇ H₃₀ BrN₃ O: Theory: C, 65.85; H, 6.14; N, 8.53. Found:C, 65.74; H, 6.20; N, 8.32.

EXAMPLE 143

1-(2-bromobenzyl)-2-(3,4-dimethylphenyl)-6-[3-(N,N-dimethylamino)propoxy]benzimidazole.MS 491, 493.

Analysis for C₁₁ H₁₄ N₂ O₄ S: Theory: C, 65.85; H, 6.14; N, 8.53. Found:C, 66.12; H, 6.20; N, 8.49.

EXAMPLE 145

1-(2-bromomethylbenzyl)-2-(3,5-dimethylphenyl)-6-hydroxybenzimidazole

The title compound was prepared essentially as described in Example 114,supra, except that 3,5-dimethylbenzoyl chloride was employed instead of3,4,5-trimethoxybenzoyl chloride. mp 213° C., MS 406, 408, NMR, IR.

Analysis for C₂₂ H₁₉ BrN₂ O: Theory: C, 64.88; H, 4.70; N, 6.88. Found:C, 64.74; H, 4.80; N, 7.01.

The following compounds were prepared essentially as described supra,except that the compound of Example 145 was employed as a startingmaterial.

EXAMPLE 146

1-(2-bromobenzyl)-2-(3,5-dimethylphenyl)-6-[2-(piperidin1-yl)ethoxy]benzimidazole

IR, NMR, MS 517, 519, mp 112° C.

Analysis for C₂₉ H₃₂ BrN₃.0.5 H₂ O: Theory: C, 66.03; H, 6.31; N, 7.97.Found: C, 66.17; H, 6.50; N, 7.46.

EXAMPLE 147

1-(2-bromobenzyl)-2-(3,5-dimethylphenyl)-6-[2-(N,N-dimethylamino)ethoxy]benzimidazole

MS 477, 479.

Analysis for C₂₆ H₂₈ BrN₃ O . H₂ O: Theory: C, 62.90; H, 6.09; N, 8.46.Found: C, 63.09; H, 5.95; N, 8.45.

EXAMPLE 148

1-(2-bromobenzyl)-2-(3,5-dimethylphenyl)-6-[1-methyl-2-(N,N-dimethylamino)ethoxy]benzimidazole.mp 78° C., NMR, IR, MS 491, 493.

Analysis for C₂₇ H₃₀ BrN₃ O: Theory: C, 65.85; H, 6.14; N, 8.53. Found:C, 66.05; H, 6.15; N, 8.80.

EXAMPLE 149

1-(2-bromobenzyl)-2-(3,5-dimethylphenyl)-6-[2-(N,N-diisopropylamino)ethoxy]benzimidazole

MS 534, 536.

Analysis for C₃₀ H₃₆ BrN₃ O: Theory: C, 67.41; H, 6.79; N, 7.86. Found:C, 67.34; H, 6.87; N, 7.62.

EXAMPLE 150

1-(2-bromobenzyl)-2-(3,5-dimethylphenyl)-6-[3-(N,N-dimethylamino)propoxy]benzimidazole.MS 491, 493.

Analysis for C₂₇ H₃₀ BrN₃ O: Theory: C, 65.85; H, 6.14; N, 8.53. Found:C, 65.68; H, 6.19; N, 8.53.

EXAMPLE 151

1-phenyl-2-[3-[2-piperidin-1-yl)ethoxy]phenyl]-benzimidazole

The title compound was prepared by reacting the compound of Example 34with 2-(piperdin-1-yl)ethyl chloride in acetone and potassium carbonateas previously described. mp 68° C., IR, NMR, MS 397.

Analysis for C₂₆ H₂₇ N₃ O: Theory: C, 78.56; H, 6.85; N, 10.57. Found:C, 78.41; H, 6.90; N, 10.45.

EXAMPLE 152

1-phenyl-2-[4-[2-(piperidin-1-yl)ethoxy]phenyl]-benzimidazole

The title compound was prepared by reacting the compound of Example 29with 2-(piperdin-1-yl)ethyl chloride in acetone and potassium carbonateas previously described. mp 107° C., NMR, MS 397.

Analysis for C₂₆ H₂₇ N₃ O: Theory: C, 78.56; H, 6.85; N, 10.57. Found:C, 78.79; H, 7.12; N, 10.51.

EXAMPLE 153

1-phenyl-2-[4-[3-(piperidin-1-yl)propoxy]phenyl]-benzimidazole

The title compound was prepared by reacting the compound of Example 29with 3-(piperdin-1-yl)propyl chloride in acetone and potassium carbonateas previously described. mp 86° C., NMR, MS 412.

Analysis for C₂₇ H₂₉ N₃ O: Theory: C, 78.80; H, 7.10; N, 10.21. Found:C, 79.01; H, 7.18; N, 10.20.

EXAMPLE 154

Synthesis of 1-phenyl-2-(3,4-dimethylphenyl)-6-hydroxybenzimidazole

The title compound was prepared by first reacting1-chloro-3,4-dinitrobenzene (100 g, 0.50 mole) with aniline (140 ml,1.54 moles) in ethanol (95%, 550 ml). This reaction mixture was stirredat room temperature for about 72 hours. The resulting1-chloro-3-phenylamino-4-nitrobenzene was purified by first filteringthe orange crystals, followed by washing with hexanes. The crystals werethen dried at 80° C. for about 4 hours. Additional product was recoveredfrom the hexanes filtrate by recrystallizing from ethanol.

The 1-chloro-3-phenylamino-4-nitrobenzene was then reacted with twomolar equivalents of sodium methoxide, the sodium methoxide beingprepared essentially as described in Kottenhahn, et al., Journal ofOrganic Chemistry 28:3114 (1963). Metallic sodium (5.0 g, 217 mmol) wasadded slowly to methanol (400 ml). After all of the sodium had gone intosolution, the 1-chloro-3-phenylamino-4-nitrobenzene was added and thered-orange solution was heated to reflux and maintained at thattemperature overnight. The gold crystals of1-methoxy-3-phenylamino-4-nitrobenzene were recovered by filtration,washed with water (2 liters) and dried in vacuo.

The nitro group of the above-described intermediate was then reduce toan amino group by catalytic hydrogenation using a palladium on activatedcarbon catalyst, essentially as previously described, resulting in3-phenylamino-4-methoxyaniline with was then reacted with3,4-dimethylbenzoyl chloride as previously described. This intermediatewas then cyclized to the corresponding benzimidazole with phosphorousoxychloride as previously described to yield1-phenyl-2-(3,4-dimethylphenyl)-6-methoxybenzimidazole.

This intermediate was then reacted with hydrobromic acid (48%) andglacial acetic acid under nitrogen atmosphere to cleave the methoxygroup from the 6-position of the benzimidazole. The resulting titlecompound was purified by adding the reaction mixture to one liter ofwater and extracting with methylene chloride (3×500 ml). The organicfractions were combined, dried over magnesium sulfate and the solventswere removed in vacuo to yield reddish solid crystals. The crystals werewashed with water (3×250 ml) to remove excess hydrobromic acid and thendried, followed by washing with diethyl ether (2×250 ml) and drying invacuo. mp 251° C., IR, NMR, MS 314.

Analysis for C₂₁ H₁₈ N₂ O: Theory: C, 80.23; H, 5.77; N, 8,91. Found: C,79.98; H, 5.77; N, 8.94.

EXAMPLE 155

1-phenyl-2-(3,4-dimethylphenyl)-6-[2-(piperidin-1-yl)ethoxy]benzimidazole

The title compound was prepared by reacting the compound of Example 154,supra, with 2-(piperidin-1-yl)ethyl chloride as previously described.NMR, IR, MS 425, mp 111° C.

Analysis for C₂₈ H₃₁ N₃ O . 0.5 H₂ O: Theory: C, 77.39; H, 7.42; N,9.67. Found: C, 77.38; H, 7.24; N, 10.36.

The following compounds were prepared essentially as described above:

EXAMPLE 156

1-Benzyl-2-phenylbenzimidazole

EXAMPLE 157

1-(1-Diethylaminopent-4-yl)-2-(3-nitrophenyl)benzimidazole

EXAMPLE 158

1-(1-Diethylaminopent-4-yl)-2-(4-methoxyphenyl)-benzimidazole

EXAMPLE 159

1-(1-Dimethylaminoethyl)-2-phenylbenzimidazole

EXAMPLE 160

1-(1-Dimethylaminopropyl)-2-benzylbenzimidazole

EXAMPLE 161

1-(4-chlorophenylmethyl)-2-(4-chlorophenylmethyl)-benzimidazole. mp89-90° C.

EXAMPLE 162

1-phenyl-2-(4-chlorophenyl)-6-methoxybenzimidazole. mp 171-172.5° C.

EXAMPLE 163

1-phenyl-2-(4-chlorophenyl)-5-(1-ethylaminoethyl)-benzimidazole,(Z)-2-butenedioic acid salt. mp 228° C.

EXAMPLE 164

1-phenyl-2-(4-chlorophenyl)-6-chlorobenzimidazole. mp 210-212° C.

EXAMPLE 165

1-phenyl-2-(4-chlorophenyl)-6-(imidazol-1-yl)benzimidazole. mp 223° C.

EXAMPLE 166

1-phenyl-2-(4-chlorophenyl)-5-nitrobenzimidazole. mp 194° C.

EXAMPLE 167

1-phenyl-2-(4-chlorophenyl)-6-hydroxyethylamino-benzimidazole. mp 225°C.

EXAMPLE 168

1-phenyl-2-(4-chlorophenyl)-5-(1-aminoethyl)benzimidazole,(Z)-2-butenedioic acid salt. mp 206° C.

EXAMPLE 169

1-phenyl-2-(4-chlorophenyl)-6-(N-isopropylcarbonyl-N-butylamino)benzimidazole.bp 213-220°C.

EXAMPLE 170

1-phenyl-2-(4-chlorophenyl)-5-acetylbenzimidazole. mp 159° C.

EXAMPLE 171

1-phenyl-2-(4-chlorophenyl)-5-(2-hydroxyethyl)benzimidazole. mp 165° C.

EXAMPLE 172

1-phenyl-2-(4-chlorophenyl)-6-[2-(piperidin-1-yl)ethoxy]benzimidazole.mp 138-140.

EXAMPLE 173

1-phenyl-2-(4-chlorophenyl)-6-[3-(N,N-dimethylamino)propoxy]benzimidazole.mp 126° C.

EXAMPLE 174

1-phenyl-2-(4-hydroxyphenyl)-6-hydroxybenzimidazole, hydrochloride. mp212° C.

The other compounds of Formula I may be prepared essentially asdescribed above, employing corresponding starting materials.

The biological efficacy of a compound believed to be effective as atachykinin receptor antagonist may be confirmed by employing an initialscreening assay which rapidly and accurately measured the binding of thetested compound to known NK-1 and NK-2 receptor sites. Assays useful forevaluating tachykinin receptor antagonists are well known in the art.See. e.g., J. Jukic, et al., Life Sciences, 49:1463-1469 (1991); N.Kulcharczyk, et al., Journal of Medicinal Chemistry, 36:1654-1661(1993); N. Rouissi, et al., Biochemical and Biophysical ResearchCommunications 176:894-901 (1991).

NK-1 Receptor Binding Assay

Radioreceptor binding assays were performed using a derivative of apreviously published protocol. D. G. Payan, et al., Journal ofImmunology, 133:3260-3265 (1984). In this assay an aliquot of IM9 cells(1×10⁶ cells/tube in RPMI 1604 medium supplemented with 10% fetal calfserum) was incubated with 20 pM ¹²⁵ I-labeled substance P in thepresence of increasing competitor concentrations for 45 minutes at 4° C.

The IM9 cell line is a well-characterized cell line which is readilyavailable to the public. See. e.g., Annals of the New York Academy ofScience, 190: 221-234 (1972); Nature (London) 251:443-444 (1974);Proceedings of the National Academy of Sciences (USA), 71:84-88 (1974).These cells were routinely cultured in RPMI 1640 supplemented with 50μg/ml gentamicin sulfate and 10% fetal calf serum.

The reaction was terminated by filtration through a glass fiber filterharvesting system using filters previously soaked for 20 minutes in 0.1%polyethylenimine. Specific binding of labeled substance P was determinedin the presence of 20 nM unlabeled ligand.

Many of the compounds employed in the methods of the present inventionare also effective antagonists of the NK-2 receptor.

NK-2 Receptor Binding Assay

The CHO-hNK-2R cells, a CHO-derived cell line transformed with the humanNK-2 receptor, expressing about 400,000 such receptors per cell, weregrown in 75 cm² flasks or roller bottles in minimal essential medium(alpha modification) with 10% fetal bovine serum. The gene sequence ofthe human NK-2 receptor is given in N. P. Gerard, et al., Journal ofBiological Chemistry, 265:20455-20462 (1990).

For preparation of membranes, 30 confluent roller bottle cultures weredissociated by washing each roller bottle with 10 ml of Dulbecco'sphosphate buffered saline (PBS) without calcium and magnesium, followedby addition of 10 ml of enzyme-free cell dissociation solution(PBS-based, from Specialty Media, Inc.). After an additional 15 minutes,the dissociated cells were pooled and centrifuged at 1,000 RPM for 10minutes in a clinical centrifuge. Membranes were prepared byhomogenization of the cell pellets in 300 ml 50 mM Tris buffer, pH 7.4with a Tekmar® homogenizer for 10-15 seconds, followed by centrifugationat 12,000 RPM (20,000×g) for 30 minutes using a Beckman JA-14® rotor.The pellets were washed once using the above procedure and the finalpellets were resuspended in 100-120 ml 50 mM Tris buffer, pH 7.4, and 4ml aliquots stored frozen at -70° C. The protein concentration of thispreparation was 2 mg/ml.

For the receptor binding assay, one 4-ml aliquot of the CHO-hNK-2Rmembrane preparation was suspended in 40 ml of assay buffer containing50 mM Tris, pH 7.4, 3 mM manganese chloride, 0.02% bovine serum albumin(BSA) and 4 μg/ml chymostatin. A 200 μl volume of the homogenate (40 μgprotein) was used per sample. The radioactive ligand was [¹²⁵I]iodohistidyl-neurokinin A (New England Nuclear, NEX-252), 2200Ci/mmol. The ligand was prepared in assay buffer at 20 nCi per 100 μl;the final concentration in the assay was 20 pM. Non-specific binding wasdetermined using 1 μM eledoisin. Ten concentrations of eledoisin from0.1 to 1000 nM were used for a standard concentration-response curve.

All samples and standards were added to the incubation in 10 μldimethylsulfoxide (DMSO) for screening (single dose) or in 5 μl DMSO forIC₅₀ determinations. The order of additions for incubation was 190 or195 μl assay buffer, 200 μl homogenate, 10 or 5 μl sample in DMSO, 100μl radioactive ligand. The samples were incubated 1 hr at roomtemperature and then filtered on a cell harvester through filters whichhad been presoaked for two hours in 50 mM Tris buffer, pH 7.7,containing 0.5% BSA. The filter was washed 3 times with approximately 3ml of cold 50 mM Tris buffer, pH 7.7. The filter circles were thenpunched into 12×75 mm polystyrene tubes and counted in a gamma counter.

It has been determined that the method of the present invention iseffective in treating mammals, particularly middle-aged women,exhibiting symptoms of interstitial cystitis and/or urethral syndrome.In this regard, the clinical and local immune response to the compoundsof the present invention is investigated in an open trail with 10 femaleinterstitial cystitis patients, whose disease is diagnosed according tothe consensus criteria developed in 1987 at a National Institutes ofHealth workshop. To make objective the symptoms and the clinicalresponse of the patients the present inventors scored (scale 0 to 2) thesymptoms of frequency, urgency, nocturia, dysuria and suprapubic pain,as described in U.S. Pat. No. 5,145,859, issued Sep. 8, 1992, the entirecontents of which are herein incorporated by reference. A compound ofthe present invention is administered as a single daily dose determinedby a dose-titration test. Urinary interleukin-2 inhibitory activity(IL-2-IN), a marker of cell-mediated inflammation, is measured using amurine interleukin-2 dependent cell line.

The patients are reviewed for reduction in clinical symptoms. Drugside-effects are minimal. Urinary IL-2-IN activity before therapyconfirms the presence of cell-mediated inflammation: after 4 months oftherapy IL-2-IN activity is normal in most of the patients, regardlessof the severity of symptoms, which indicates that the compounds ofFormula I exerts an immunosuppressive effect. The data suggests that thecompounds of Formula I can be an efficacious, well-tolerated, convenientoral medication for the treatment of interstitial cystitis.

In addition, as more clearly demonstrated below in Example 2, thepresent inventors also observes similar responses in regard to thetreatment of urethral syndrome. As a result, the test data clearlyindicates that the compounds employed in the present invention can beeffective therapeutic agents for the treatment of interstitial cystitisand/or urethral syndrome.

As a result, it has been found that compounds of Formula I areparticularly well-suited for the treatment of interstitial cystitisand/or urethral syndrome because they not only provide effective relief,are available for oral administration, and are relatively inexpensive.It has been discovered that patients receiving the compounds of FormulaI substantially reduce the pathological conditions exhibited by thesetwo painful bladder disorders, and are able to carry on their dailyactivities in a relatively normal existence in comparison with theirpre-treatment state.

The present invention will be further described according to thefollowing non-limiting examples.

EXAMPLE 1

Materials and Methods

Patients. The diagnosis of interstitial cystitis is assigned to 10female patients, aged 23 to 51 years, in accordance with the consensuscriteria established at the National Institutes of Health workshop oninterstitial cystitis, August, 1987 (Gillenwater, J. Y. and Wein, A J.:Summary of the National Institute of Arthritis, Diabetes, Digestive andKidney Diseases Workshop on Interstitial Cystitis, National Institutesof Health, Bethesda, Md., Aug. 28-29, 1987, J. Urol., 140:203, 1988),and U.S. Pat. No. No. 5,145,859:

Interstitial Cystitis: Criteria for Diagnosis

    ______________________________________                                        Inclusion Criteria                                                                              Exclusion Criteria                                          ______________________________________                                        Hunner's Ulcer (if present,                                                                     less than 18 years old                                      automatic inclusion)                                                                                           benign or malignant tumors                                                                        radiation,                                 tuberculous,                                                                                                     bacterial                Positive Factors (at least 2                                                                           or cyclophosphamide cystitis                         required for inclusion):                                                                                   vaginitis                                                                                             duration of symptoms                       <1 year                                                     suprapubic, pelvic, urethral,                                                                         gynecologic cancer                                    vaginal or perineal pain                                                                                   urethral diverticulum, bladder                                                                        or lower ureteral                          calculi                                                     glomerulations at cystoscopy                                                                           active herpes (HSV II)                               after bladder distension                                                                                   waking frequency <5 in 12 hrs.                   (80 cm water pressure × 1 min.)                                                           nocturia <2                                                                                                      neurogenic bladder                         dysfunction                                                 decreased compliance on                                                                                     waking capacity >400 ml,                        cystometrogram                         absence of urgency with bladder                                                             filling symptoms                           relieved                                                                                                         by antibiotics,                            urinary                                                     pain on bladder filling                                                                                     urinary analgesics or                           relieved by emptying                                                                                           antiseptics                                  ______________________________________                                    

Cystometrics are performed after cessation of other modes of therapy andprior to institution of therapy: all patients had a waking bladdercapacity of less than 350 ml (range 150 ml to 340 ml).

Symptom Evaluation: The symptom scores (total score range: 0 to 10) formthe basis for the evaluation of treatment efficacy. The severity of eachsymptom is assigned a numerical value, as follows:

Symptom Severity Survey

    ______________________________________                                        Symptom     Description         Score                                         ______________________________________                                        Frequency   voids once every 3 to 5 hours                                                                     0                                             (daytime)              voids once every 1 to 2 hours                                                                1                                                                       voids more than once every                                                        2                                         Urgency                  urge to void equal to actual frequency                                                  0                                                                          urge to void exceeds actual                                                       1ency                                                                     constant urge to void                                                                       2                               Nocturia                no nocturia, or 1 void nightly                                                             0                                                                        nocturia 2 to 4 times nightly                                                       1                                                                       more than 4 times nightly                                                               2                                   Dysuria                  no dysuria                                                                                                    0                                                    intermittent dysuria                                                                         1                                                              dysuria with each void                                                                     2                                Suprapubic pain                                                                                no pain                                    0                 (abdomino-            intermittent pain                                                                                         1                           perineal)              constant pain                                                                                                2                       ______________________________________                                    

At the time of diagnosis, and before any treatment, any patient whofalls within the parameters of the inclusion of exclusion descriptors ofthe NIH workshop consensus criteria (above) will score at least a "4" onthis survey (frequency<1; urgency<1; nocturia<1; and either dysuria orsuprapubic pain<1).

Urine Collection: Urine specimens are collected from all patients beforeand during therapy. Voided urine is centrifuged at 1000×g for 10 minutesat 4° C. and the supernatant separated from the sediment. The urinesupernatant is subjected to 0.2μ filtration (celluloseacetate) at 4° C.to remove any bacteria and debris, and a 1 ml aliquot is removed forcreatinine measurement (CREATININE II ANALYZER™, Beckman Instruments,Inc., Brea, Calif.). The supernatant is ultrafiltered against 3×volumein phosphate-buffered saline (PBS) with 0.1 μg/ml albumin (Sigma, St.Louis, Miss.) using a filtration device (5,000 MW cut off, Amicon,Deavers, Mass.). The concentrated supernatant is dialyzed using 3,500 MWcutoff tubing, shell frozen with dry ice, and vacuum lyophilized. Thepowder is stored at -20° C.

Measurement of IL-2-IN Activity: The bioassay for IL-2-IN is modifiedfrom the method for measuring IL-2 activity described by Gillis andassociates. S. Gillis, et al., "T-Cell Growth Factor: Parameters OfProduction And A Quantitative Microassay For Activity, Journal ofImmunology, 120:2027, (1978). The murine IL-2-dependent cytotoxic T-cellline (CTLL-N) is derived from the CT-6 cell line. J. Kusugami, et al.,"Intestinal Immune Reactivity To Interleukin-2 Differs Among Crohn'sDisease, Ulcerative Colitis And Controls", Gastroenterology 97:1 (1989).The CTTL-Ns are maintained in liquid culture using a 1:1 mixture ofRoswell Park Memorial Institute (RPMI) 1640 and Dulbecco's ModifiedEagles Medium (DMEM; 4.5 g/L glucose) media supplemented with 2.9 mg/mlglucose, 9.4 mM HEPES buffer, 1.9 mg/ml glutamine, 289 μg/ml arginine,0.12 M non-essential amino acids, 5×10⁻⁵ M 2-mercaptoethanol, 4.5% fetalbovine serum, 90 units/ml penicillin, 90 μg/ml streptomycin, 22 μg/mlfungizone, 0.45 mg/ml gentamicin and 20 units/ml of human recombinantIL-2.

The CTLL-Ns are washed and suspended at a concentration of 10⁻⁵ /ml inthe culture media. Assays are performed in triplicate, as follows: aserial dilution of the sample aliquot (50 μl), a 1:10 dilution of thehuman recombinant IL-2 standard and 10⁻⁴ CTLL-Ns (100 μl) are placed inmicroliter wells. The microliter plates are incubated in a humidified 6%CO₂ atmosphere at 37° C. for 24 hrs, and the cells are pulsed at the19th hour with 1 μCi/well of methyl-tritiated thymidine (specificactivity 6.7 Ci/mM, New England Nuclear, I. E. Dupont, Boston, Mass.).

The cells are collected onto glass filter paper discs. The discs areplaced in scintillation fluid and thymidine uptake is measured by liquidscintillation spectrophotometry. IL-2 inhibitory activity is calculatedby modified probit analysis.

The proliferation "maximum" is the tritiated thymidine uptake caused bythe amount of exogenous IL-2 activity in the control microliter wells,assessed in quadruplicate for each assay. The proliferation "minimum" isderived from lowest amount of tritiated thymidine uptake caused by theIL-2 inhibitor standard. The probit calculation corrected for minorinterassay variations of thymidine uptake in control wells, andpermitted interassay comparisons of inhibitor activity among the urinesamples. By this treatment of the data, the calculated value of IL-2inhibitory activity in lyophilized urine samples varies less than 10%from assay to assay. IL-2-IN activity is expressed in units/mg urinecreatinine (U/mg u.c.). IL-2-IN activity is less than 0.05 U/mg u.c. inthe urine of healthy adults. J. Fleischmann, et al., Journal ofBiological Regulators and Homeostatic Agents, 4:73, (1990).

Medication Assignments: All patients are treated initially with a totaldaily dose of 30 mg, which is administered as a single, extended releasetablet.

Patient Monitoring: Patients are interviewed and blood pressure measuredtwice monthly during the first 2 months of therapy, during the first 2months after a dose escalation, and then once monthly thereafter. Thesymptom severity score at each interview is based on the patient'sexperiences during the previous 24 hours.

EXAMPLE 2

In addition to the treatment of patients with interstitial cystitis,patients with the urethral syndrome have been treated with a compound ofFormula I, using the titration test and treatment protocol described inU.S. Pat. No. 5,145,859. Similar to the data of Example 1, the positiveresponse to the compounds of the present invention in this limited studysupports the hypothesis that the urethralsyndrome and interstitialcystitis are both part of the same disease spectrum, perhaps as variantsof reflex sympathetic dystrophy.

The invention has been described with reference to the preferredembodiment. Obviously, modifications and alterations will occur toothers upon a reading and understanding of this specification. It isintended to include all such modifications and alterations insofar asthey come within the scope of the appended claims or the equivalentsthereof.

While it is possible to administer a compound employed in the methods ofthis invention directly without any formulation, the compounds areusually administered in the form of pharmaceutical compositionscomprising a pharmaceutically acceptable excipient and at least oneactive ingredient. These compositions can be administered by a varietyof routes including oral, rectal, transdermal, subcutaneous,intravenous, intramuscular, and intranasal. Many of the compoundsemployed in the methods of this invention are effective as bothinjectable and oral compositions. Such compositions are prepared in amanner well known in the pharmaceutical art and comprise at least oneactive compound. See. e.g., REMINGTON'S PHARMACEUTICAL SCIENCES, (16thed. 1980).

In making the compositions employed in the present invention the activeingredient is usually mixed with an excipient, diluted by an excipientor enclosed within such a carrier which can be in the form of a capsule,sachet, paper or other container. When the excipient serves as adiluent, it can be a solid, semi-solid, or liquid material, which actsas a vehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixers, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing forexample up to 10% by weight of the active compound, soft and hardgelatin capsules, suppositories, sterile injectable solutions, andsterile packaged powders.

In preparing a formulation, it may be necessary to mill the activecompound to provide the appropriate particle size prior to combiningwith the other ingredients. If the active compound is substantiallyinsoluble, it ordinarily is milled to a particle size of less than 200mesh. If the active compound is substantially water soluble, theparticle size is normally adjusted by milling to provide a substantiallyuniform distribution in the formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxybenzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 0.05 to about 100 mg, more usually about1.0 to about 30 mg, of the active ingredient. The term "unit dosageform" refers to physically discrete units suitable as unitary dosagesfor human subjects and other mammals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient.

The active compounds are generally effective over a wide dosage range.For examples, dosages per day normally fall within the range of about0.01 to about 30 mg/kg of body weight. In the treatment of adult humans,the range of about 0.1 to about 15 mg/kg/day, in single or divided dose,is especially preferred. However, it will be understood that the amountof the compound actually administered will be determined by a physician,in the light of the relevant circumstances, including the condition tobe treated, the chosen route of administration, the actual compound orcompounds administered, the age, weight, and response of the individualpatient, and the severity of the patient's symptoms, and therefore theabove dosage ranges are not intended to limit the scope of the inventionin any way. In some instances dosage levels below the lower limit of theaforesaid range may be more than adequate, while in other cases stilllarger doses may be employed without causing any harmful side effect,provided that such larger doses are first divided into several smallerdoses for administration throughout the day.

Formulation Preparation 1

Hard gelatin capsules containing the following ingredients are prepared:

    ______________________________________                                                        Quantity                                                      Ingredient                        (mg/capsule)                                ______________________________________                                        Active Ingredient(s)                                                                          30.0                                                          Starch                                305.0                                   Magnesium stearate                                                                                        5.0                                               ______________________________________                                    

The above ingredients are mixed and filled into hard gelatin capsules in340 mg quantities.

Formulation Preparation 2

A tablet formula is prepared using the ingredients below:

    ______________________________________                                                          Quantity                                                    Ingredient                     (mg/tablet)                                    ______________________________________                                        Active Ingredient(s)                                                                            25.0                                                        Cellulose, microcrystalline                                                                         200.0                                                   Colloidal silicon dioxide                                                                             10.0                                                  Stearic acid                         5.0                                      ______________________________________                                    

The components are blended and compressed to form tablets, each weighing240 mg.

Formulation Preparation 3

A dry powder inhaler formulation is prepared containing the followingcomponents:

    ______________________________________                                        Ingredient      Weight %                                                      ______________________________________                                        Active Ingredient(s)                                                                          5                                                             Lactose                                 95                                    ______________________________________                                    

The active mixture is mixed with the lactose and the mixture is added toa dry powder inhaling appliance.

Formulation Preparation 4

Tablets, each containing 30 mg of active ingredient, are prepared asfollows:

    ______________________________________                                                           Quantity                                                   Ingredient                      (mg/tablet)                                   ______________________________________                                        Active Ingredient(s)                                                                             30.0 mg                                                    Starch                                     45.0 mg                            Microcrystalline cellulose                                                                           35.0 mg                                                Polyvinylpyrrolidone                                                                                        4.0 mg                                          (as 10% solution in water)                                                    Sodium carboxymethyl starch                                                                          4.5 mg                                                 Magnesium stearate              0.5 mg                                        Talc                                          1.0 mg                          Total                                        120 mg                           ______________________________________                                    

The active ingredient, starch and cellulose are passed through a No. 20mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders, which are thenpassed through a 16 mesh U.S. sieve. The granules so produced are driedat 50-60° C. and passed through a 16 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate, and talc, previously passedthrough a No. 30 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 120 mg.

Formulation Preparation 5

Capsules, each containing 40 mg of medicament are made as follows:

    ______________________________________                                                        Quantity                                                      Ingredient              (mg/capsule)                                          ______________________________________                                        Active Ingredient(s)                                                                           40.0 mg                                                      Starch                              109.0 mg                                  Magnesium stearate                                                                                    1.0 mg                                                Total                                150.0 mg                                 ______________________________________                                    

The active ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 20 mesh U.S. sieve, and filled into hardgelatin capsules in 150 mg quantities.

Formulation Preparation 6

Suppositories, each containing 25 mg of active ingredient are made asfollows:

    ______________________________________                                        Ingredient          Amount                                                    ______________________________________                                        Active Ingredient(s)                                                                                25 mg                                                   Saturated fatty acid glycerides to                                                                  2,000 mg                                                ______________________________________                                    

The active ingredient(s) is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2.0 g capacity and allowed to cool.

Formulation Preparation 7

Suspensions, each containing 50 mg of medicament per 5.0 ml dose aremade as follows:

    ______________________________________                                        Ingredient            Amount                                                  ______________________________________                                        Active Ingredient(s)  50.0 mg                                                 Xanthan gum                            4.0 mg                                 Sodium carboxymethyl cellulose (11%)                                          Microcrystaliine cellulose (89%)                                                                    50.0 mg                                                 Sucrose                                     1.75 g                            Sodium benzoate                    10.0 mg                                    Flavor and Color                    q.v.                                      Purified water to                 5.0 ml                                      ______________________________________                                    

The medicament, sucrose and xanthan gum are blended, passed through aNo. 10 mesh U.S. sieve, and then mixed with a previously made solutionof the microcrystalline cellulose and sodium carboxymethyl cellulose inwater. The sodium benzoate, flavor, and color are diluted with some ofthe water and added with stirring. Sufficient water is then added toproduce the required volume.

Formulation Preparation 8

Capsules, each containing 15 mg of medicament, are made as follows:

    ______________________________________                                                        Qualitity                                                     Ingredient              (mg/capsule)                                          ______________________________________                                        Active Ingredient(s)                                                                           15.0 mg                                                      Starch                          407.0 mg                                      Magnesium stearate                                                                                 3.0 mg                                                   Total                            425.0 mg                                     ______________________________________                                    

The active ingredient(s), cellulose, starch, and magnesium stearate areblended, passed through a No. 20 mesh U.S. sieve, and filled into hardgelatin capsules in 425 mg quantities.

Formulation Preparation 9

An intravenous formulation may be prepared as follows:

    ______________________________________                                        Ingredient      Quantity                                                      ______________________________________                                        Active Ingredient(s)                                                                          250.0 mg                                                      Isotonic saline          1000 ml                                              ______________________________________                                    

Formulation Preparation 10

A topical formulation may be prepared as follows:

    ______________________________________                                        Ingredient      Quantity                                                      ______________________________________                                        Active Ingredient(s)                                                                          1-10 g                                                        Emulsifying Wax           30 g                                                Liquid Paraffin           20 g                                                White Soft Paraffin                                                                                 to 100 g                                                ______________________________________                                    

The white soft paraffin is heated until molten. The liquid paraffin andemulsifying wax are incorporated and stirred until dissolved. The activeingredient is added and stirring is continued until dispersed. Themixture is then cooled until solid.

Formulation Preparation 11

Sublingual or buccal tablets, each containing 10 mg of activeingredient, may be prepared as follows:

    ______________________________________                                                         Quantity                                                     Ingredient                    Per Tablet                                      ______________________________________                                        Active Ingredient(s)                                                                            10.0 mg                                                     Glycerol                        210.5 mg                                      Water                              143.0 mg                                   Sodium Citrate             4.5 mg                                             Polyvinyl Alcohol                                                                                     26.5 mg                                               Polyvinylpyrrolidone                                                                               15.5 mg                                                  Total                              410.0 mg                                   ______________________________________                                    

The glycerol, water, sodium citrate, polyvinyl alcohol, andpolyvinylpyrrolidone are admixed together by continuous stirring andmaintaining the temperature at about 90° C. When the polymers have goneinto solution, the solution is cooled to about 50-55° C. and themedicament is slowly admixed. The homogenous mixture is poured intoforms made of an inert material to produce a drug-containing diffusionmatrix having a thickness of about 2-4 mm. This diffusion matrix is thencut to form individual tablets having the appropriate size.

Another preferred formulation employed in the methods of the presentinvention employs transdermal delivery devices ("patches"). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of the compounds of the present invention in controlledamounts. The construction and use of transdermal patches for thedelivery of pharmaceutical agents is well known in the art. See, e.g.,U.S. Pat. No. 5,023,252, issued Jun. 11, 1991, herein incorporated byreference. Such patches may be constructed for continuous, pulsatile, oron demand delivery of pharmaceutical agents.

Frequently, it will be desirable or necessary to introduce thepharmaceutical composition to the brain, either directly or indirectly.Direct techniques usually involve placement of a drug delivery catheterinto the host's ventricular system to bypass the blood-brain barrier.One such implantable delivery system, used for the transport ofbiological factors to specific anatomical regions of the body, isdescribed in U.S. Pat. No. 5,011,472, issued Apr. 30, 1991, which isherein incorporated by reference.

Indirect techniques, which are generally preferred, usually involveformulating the compositions to provide for drug latentiation by theconversion of hydrophilic drugs into lipid-soluble drugs or prodrugs.Latentiation is generally achieved through blocking of the hydroxy,carbonyl, sulfate, and primary amine groups present on the drug torender the drug more lipid soluble and amenable to transportation acrossthe blood-brain barrier. Alternatively, the delivery of hydrophilicdrugs may be enhanced by intra-arterial infusion of hypertonic solutionswhich can transiently open the blood-brain barrier.

We claim:
 1. A method for the treatment or prevention of interstitialcystitis or urethral syndrome in a mammal which comprise administeringto a mammal in need thereof an effective amount of a compound of theformula ##STR11## wherein: R¹ is hydrogen, C₁ -C₁₂ alkyl, C₁ -C₆ alkoxy,phenyl, C₃ -C₈ cycloalkyl, naphthyl, heterocyclic, unsaturatedheterocyclic, phenyl-(C₁ -C₆ alkylidenyl)-, naphthyl-(C₁ -C₆alkylidenyl)-, heterocyclic-(C₁ -C₆ alkylidenyl)-, unsaturatedheterocyclic-(C₁ -C₆ alkylidenyl)-, phenyl-(C₁ -C₆ alkoxy)-,naphthyl-(C₁ -C₆ alkoxy)-, heterocyclic-(C₁ -C₆ alkoxy)-, or unsaturatedheterocyclic-(C₁ -C₆ alkoxy)-,any one of which phenyl, naphthyl,heterocyclic, C₃ -C₈ cycloalkyl, or unsaturated heterocyclic groups maybe optionally substituted with one, two, or three moieties independentlyselected from group consisting of heterocyclic-(C₁ -C₆ alkylidenyl)-,unsaturated heterocyclic-(C₁ -C₆ alkylidenyl)-, hydroxy, halo, C₁ -C₆alkyl, C₁ -C₆ alkoxy, trifluoromethyl, nitro, amino, cyano, C₁ -C₆alkylamino, and C₁ -C₆ alkylthio; R² is hydrogen, C₁ -C₁₂ alkyl, C₁ -C₆alkoxy, phenyl, C₃ -C₈ cycloalkyl, naphthyl, heterocyclic, unsaturatedheterocyclic, phenyl-(C₁ -C₆ alkylidenyl)-, naphthyl-(C₁ -C₆alkylidenyl)-, heterocyclic-(C₁ -C₆ alkylidenyl)-, unsaturatedheterocyclic-(C₁ -C₆ alkylidenyl)-, phenyl-(C₁ -C₆ alkoxy)-,naphthyl-(C₁ -C₆ alkoxy)-, heterocyclic-(C₁ -C₆ alkoxy)-, or unsaturatedheterocyclic-(C₁ -C₆ alkoxy)-,any one of which phenyl, naphthyl,heterocyclic, C₃ -C₈ cycloalkyl, or unsaturated heterocyclic groups maybe optionally substituted with one, two, or three moieties independentlyselected from group consisting of phenyl-(C₁ -C₆ alkylidenyl)-,naphthyl-(C₁ -C₆ alkylidenyl)-, heterocyclic-(C₁ -C₆ alkylidenyl)-,unsaturated heterocyclic-(C₁ -C₆ alkylidenyl)-, phenyl-(C₁ -C₆ alkoxy)-,naphthyl-(C₁ -C₆ alkoxy)-, heterocyclic-(C₁ -C₆ alkoxy)-, or unsaturatedheterocyclic-(C₁ -C₆ alkoxy)-, hydroxy, halo, C₁ -C₆ alkyl, C₁ -C₆alkoxy, trifluoromethyl, nitro, amino, cyano, C₁ -C₆ alkylamino, and C₁-C₆ alkylthio; R³ is hydrogen, nitro, C₁ -C₆ alkanoyl, amino, C₁ -C₆alkyl, C₁ -C₆ alkoxy, C₃ -C₈ cycloalkyl, heterocyclic, unsaturatedheterocyclic, halo, C₁ -C₆ alkylthio, hydroxy-(C₁ -C₆ alkylidenyl)-,hydroxy-(C₁ -C₆ alkylidenyl)amino-, R⁴ R⁵ N-, R⁴ R⁵ N-(C₁ -C₆alkylidenyl)-, R⁴ R⁵ N-(C₁ -C₆ alkoxy)-, hydroxy-(C₁ -C₆ alkyl)-,heterocyclic-(C₁ -C₆ alkoxy)-, amino(C₁ -C₆ alkylidenyl)-, ortrifluoromethyl,where R⁴ and R⁵ are independently selected from thegroup consisting of C₁ -C₆ alkyl, C₁ -C₆ alkoxy, C₁ -C₆ alkanoyl, aryl,heterocyclic, unsaturated heterocyclic, aryl(C₁ -C₆ alkylidenyl)-,heterocyclic(C₁ -C₆ alkylidenyl)-, unsaturated heterocyclic(C₁ -C₆alkylidenyl)-, and hydrogen or R⁴ and R⁵ combine to form C₃ -C₈cycloalkyl, any one of which alkyl or alkoxy groups may be substitutedwith one or more halo, amino, or nitro, and any one of which aryl,unsaturated heterocyclic, or heterocyclic groups may be substituted withone, two, or three moieties independently selected from group consistingof hydroxy, halo, C₁ -C₆ alkyl, C₁ -C₆ alkoxy, trifluoromethyl, nitro,amino, cyano, C₃ -C₈ cycloalkyl, C₁ -C₆ alkylamino, and C₁ -C₆alkylthio; with the proviso that not more than one of R¹ and R² may behydrogen;or a pharmaceutically acceptable salt or solvate thereof.
 2. Amethod as claimed in claim 1 employing employing1-benzyl-2-(3,4,5-trimethoxyphenyl)-6-[2-(4-morpholinyl)ethoxy]benzimidazole,1-benzyl-2-(3,4,5-trimethoxyphenyl)-6-[2-(1-piperidinyl)ethoxy]benzimidazole,1-benzyl-2-(3,4,5-trimethoxyphenyl)-6-[2-(1-pyrroldinyl)ethoxy]benzimidazole,1-benzyl-2-(3,4,5-trimethoxyphenyl)-6-[2-(1-hexamethyleneiminyl)ethoxy]benzimidazole,1-benzyl-2-(3,4,5-trimethoxyphenyl)-6-[3-(1-piperidinyl)propoxy]benzimidazole,1-benzyl-2-(3,4,5-trimethoxyphenyl)-6-[2-[4-(piperidin-1-yl)piperdin-1-yl]ethoxy]benzimidazole,1-benzyl-2-(3,4,5-trimethoxyphenyl)-6-[2-(4-methyl-1-piperazinyl)ethoxy]benzimidazole,1-benzyl-2-(3-methylphenyl)-6-[2-(1-pyrrolidinyl)ethoxy]benzimidazole,1-benzyl-2-(3-methylphenyl)-6-[3-(piperdin-1-yl)propoxy]-benzimidazole,1-benzyl-2-(3-methylphenyl)-6-[3-(morpholin-4-yl)propoxy)benzimidazole,1-benzyl-2-(3-methylphenyl)-6-[3-(pyrrolidin-1-yl)propoxy)benzimidazole,1-benzyl-2-(3-methylphenyl)-6-[3-(hexamethyleneimin-1-yl)propoxy)benzimidazole,1-benzyl-2-(3-methylphenyl)-6-[3-heptamethyleneimin-1-yl)propoxy)benzimidazole,1-benzyl-2-(3-methylphenyl)-6-[2-(4-methyl-piperazin-1-yl)ethoxy]benzimidazole,1-(2-trifluoromethylbenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2-(piperidin-1-yl)ethoxy]benzimidazole,1-(2-trifluoromethylbenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[3-(piperidin-1-yl)propoxy]benzimidazole,1-(2-trifluoromethylbenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2-(hexamethyleneimin-1-yl)ethoxy]benzimidazole,1-(2-trifluoromethylbenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2-(pyrrolidin-1-yl)ethoxy]benzimidazole,1-(2-trifluoromethylbenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2-(morpholin-4-yl)ethoxy]benzimidazole,1-(2-bromobenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2-(piperdin-1-yl)ethoxy]benzimidazole,1-(2-trifluoromethylbenzyl)-2-(3-methylphenyl)-6-[2-(piperidinyl-1-yl)ethoxy]benzimidazole,1-(2-bromobenzyl)-2-(3-methylphenyl)-6-[2-(piperidinyl-1-yl)ethoxy]benzimidazole,1-(2-trifluoromethylbenzyl)-2-(3,4dimethylphenyl)-6-[2-piperidin-1-yl)ethoxy]benzimidazole,1-(2-bromobenzyl)-2-(3,4-dimethylphenyl)-6-[2-(piperidin-1-yl)ethoxy]benzimidazole,or1-(2-bromobenzyl)-2-(3,5-dimethylphenyl)-6-[2-(piperidin-1-yl)ethoxy]benzimidazole,or a pharmaceutically acceptable salt or solvate thereof.
 3. A method asclaimed in claim 1 employing employing1-benzyl-2-(3,4,5-trimethoxyphenyl)-6-[1-methyl-2-(N,N-dimethylamino)]ethoxy]benzimidazole,1-benzyl-2-(3,4,5-trimethoxyphenyl)-6-[2-(N,N-dimethylamino)ethoxy]benzimidazole,1-benzyl-2-(3,4,5-trimethoxyphenyl)-6-[3-(N,N-dimethylamino)propoxy]benzimidazole,1-benzyl-2-(3,4,5-timethoxyphenyl)-6-[2-(N,N-diisopropylamino)ethoxy]benzimidazole,1-benzyl-2-(3-methylphenyl)-6-[2-(N,N-dimethylamino)ethoxy]benzimidazole,1-benzyl-2-(3-methylphenyl)-6-[2-(N,N-diethylamino)ethoxy]-benzimidazole,1-benzyl-2-(3-methylphenyl)-6-[3-(N,N-dimethylamino)propoxy]benzimidazole,1-benzyl-2-(3-methylphenyl)-6-[2-(N,N-isopropylamino)ethoxy]benzimidazole,1-benzyl-2-(3-methylphenyl)-6-[2-(N,N-dibenzylamino)ethoxy]benzimidazole,1-benzyl-2-(3-methylphenyl)-6-[3-(N,N-dimethylamino)propoxy]benzimidazole,1-benzyl-2-(3-methylphenyl)-6-[2-(N,N-dimethylamino)propoxy]-benzimidazole,1-(2-trifluoromethylbenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2-(N,N-dimethylamino)propoxy]-benzimidazole,1-(2-trifluoromethylbenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2-(N,N-dimethylamino)ethoxy]-benzimidazole,1-(2-trifluoromethylbenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[3-(N,N-dimethylamino)propoxy]-benzimidazole,1-(2-trifluoromethylbenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2-(N,N-diisopropylamino)ethoxy]benzimidazole,1-(2-bromobenzyl)-2-(3,4,5-trimethoxyphenyl-6-[2-(N,N-dimethylamino)propoxy]benzimidazole,1-(2-bromobenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2-(N,N-dimethylamino)ethoxy]benzimidazole,1-(2-bromobenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[3-(N,N-dimethylamino)propoxy]benzimidazole,1-(2-bromobenzyl)-2-(3,4,5-trimethoxyphenyl)-6-[2-(N,N-diisopropylamino)ethoxy]benzimidazole,1-(2-trifluoromethylbenzyl)-2-(3-methylphenyl)-6-[2-(N,N-dimethylamino)ethoxy]benzimidazole,1-(2-trifluoromethylbenzyl)-2-(3-methylphenyl)-6-[3-(N,N-dimethylamino)propoxy]benzimidazole,1-(2-bromobenzyl)-2-(3-methylphenyl)-6-[2-(N,N-dimethylamino)ethoxy]benzimidazole,1-(2-bromobenzyl)-2-(3-methylphenyl)-6-[3-(N,N-dimethylamino)propoxy]benzimidazole,1-(2-trifluoromethylbenzyl)-2-(3,4-dimethylphenyl)-6-[2-(N,N-dimethylamino)ethoxy]benzimidazole,1-(2-trifluoromethylbenzyl)-2-(3,4-dimethylphenyl)-6-[2-(N,N-diisopropylamino)ethoxy]benzimidazole,1-(2-bromobenzyl)-2-(3,4-dimethylphenyl)-6-[2-(N,N-dimethylamino)ethoxy]benzimidazole,1-(2-bromobenzyl)-2-(3,4-dimethylphenyl)-6-[2-(N,N-diisopropylamino)ethoxy]benzimidazole,1-(2-bromobenzyl)-2-(3,4-dimethylphenyl)-6-[1-methyl-2-(N,N-dimethylamino)ethoxy]benzimidazole,1-(2-bromobenzyl)-2-(3,5-dimethylphenyl)-6-[2-(N,N-dimethylamino)ethoxy]benzimidazole,1-(2-bromobenzyl)-2-(3,5-dimethylphenyl)-6-[1-methyl-2-(N,N-dimethylamino)ethoxy]benzimidazole,1-(2-bromobenzyl)-2-(3,5-dimethylphenyl)-6-[2-(N,N-diisopropylamino)ethoxy]benzimidazole,or1-(2-bromobenzyl)-2-(3,5-dimethylphenyl)-6-[3-(N,N-dimethylamino)propoxy]benzimidazole,or a pharmaceutically acceptable salt or solvate thereof.